U.S. patent application number 16/707277 was filed with the patent office on 2020-03-26 for compositions and methods for decolonizing antibiotic-resistant bacteria in the gut.
The applicant listed for this patent is Finch Therapeutics, Inc.. Invention is credited to Kevin ROELOFS, Marina SANTIAGO.
Application Number | 20200093870 16/707277 |
Document ID | / |
Family ID | 65272652 |
Filed Date | 2020-03-26 |
United States Patent
Application |
20200093870 |
Kind Code |
A1 |
SANTIAGO; Marina ; et
al. |
March 26, 2020 |
COMPOSITIONS AND METHODS FOR DECOLONIZING ANTIBIOTIC-RESISTANT
BACTERIA IN THE GUT
Abstract
The present invention relates to, in part, compositions and
methods for delivery of novel mixtures of bacterial strains for the
decolonization and/or eradication of various pathogenic bacteria
and, particularly, antibiotic-resistant bacteria (ARB).
Inventors: |
SANTIAGO; Marina;
(Somerville, MA) ; ROELOFS; Kevin; (Somerville,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Finch Therapeutics, Inc. |
Somerville |
MA |
US |
|
|
Family ID: |
65272652 |
Appl. No.: |
16/707277 |
Filed: |
December 9, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2018/045592 |
Aug 7, 2018 |
|
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16707277 |
|
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62542033 |
Aug 7, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/00 20180101; A61K
35/741 20130101; C12R 1/01 20130101; A61P 31/04 20180101; A61K
35/74 20130101; C07K 14/25 20130101 |
International
Class: |
A61K 35/741 20060101
A61K035/741; A61P 31/04 20060101 A61P031/04; A61P 1/00 20060101
A61P001/00 |
Claims
1.-107. (canceled)
108. A method of manufacture, the method comprising: selecting a
bacterial strain for incorporation into a pharmaceutical
composition for the treatment of a gastrointestinal disorder,
wherein the bacterial strain is from a stool of a human donor, and
wherein the bacterial strain is selected based on the presence of
the bacterial strain in a microbial composition which achieved a
therapeutically effective result when administered to one or more
patients with the gastrointestinal disorder; and incorporating the
bacterial strain into the pharmaceutical composition.
109. The method of claim 108, wherein the microbial composition
comprises fecal bacteria derived from stool of the human donor.
110. The method of claim 108, wherein the bacterial strain is
enriched in the stool of the human donor relative to a stool of the
one or more patients collected prior to said administering.
111. The method of claim 110, wherein the bacterial strain is
enriched in the stool of the human donor by at least five-fold.
112. The method of claim 108, wherein the bacterial strain is
enriched in the stool of the human donor relative to a stool of a
second human donor, wherein administration to the one or more
patients of a second microbial composition comprising fecal
bacteria derived from the stool of the second human donor does not
produce the therapeutically effective result.
113. The method of claim 112, wherein the bacterial strain is
enriched in the stool of the human donor by at least five-fold.
114. The method of claim 108, wherein the bacterial strain is
further selected based on production by the bacterial strain of a
secreted product that treats the gastrointestinal disorder.
115. The method of claim 114, wherein the secreted product is a
short-chain fatty acid (SCFA).
116. The method of claim 115, wherein the SOFA is selected from the
group consisting of formic acid, acetic acid, propionic acid,
butyric acid, isobutyric acid, valeric acid, isovaleric acid, and a
combination thereof.
117. The method of claim 108, wherein the bacterial strain is a
member of a genus selected from the group consisting of:
Odoribacter, Faecalibacterium, Alistipes, Bacteroides, Eubacterium,
Roseburia, and a combination thereof.
118. The method of claim 108, wherein incorporating the bacterial
strain into the pharmaceutical composition comprises encapsulating
the bacterial strain.
119. The method of claim 108, wherein the gastrointestinal disorder
is Inflammatory Bowel Disease (IBD) or a related disease.
120. The method of claim 108, wherein the bacterial strain
comprises a 16S rRNA sequence that is greater than about 97%
identical to the 16S rRNA sequence of any one of the operational
taxonomic units (OTUs) recited in Table 5 and/or any one OTU of a
genus recited in Table 6.
121. A method comprising: selecting a bacterial strain for
incorporation into a pharmaceutical composition for the treatment
of a gastrointestinal disorder, wherein the bacterial strain is
from a stool of a human donor, wherein the bacterial strain is
selected based on enrichment of the bacterial strain in the
intestine of one or more patients administered a microbial
composition comprising the bacterial strain, and wherein
administration of the microbial composition to the patient treated
the gastrointestinal disorder; and incorporating the bacterial
strain into the pharmaceutical composition.
122. The method of claim 121, wherein the microbial composition
comprises fecal bacteria derived from stool of the human donor.
123. The method of claim 121, wherein the bacterial strain is
further selected based on production by the bacterial strain of a
secreted product that treats the gastrointestinal disorder.
124. The method of claim 121, wherein the secreted product is a
short-chain fatty acid (SOFA).
125. The method of claim 121, wherein the bacterial strain is a
member of a genus selected from the group consisting of:
Odoribacter, Faecalibacterium, Alistipes, Bacteroides, Eubacterium,
Roseburia, and a combination thereof.
126. The method of claim 121, wherein the gastrointestinal disorder
is Inflammatory Bowel Disease (IBD) or a related disease.
127. The method of claim 121, wherein the bacterial strain
comprises a 16S rRNA sequence that is greater than about 97%
identical to the 16S rRNA sequence of any one of the operational
taxonomic units (OTUs) recited in Table 5 and/or any one OTU of a
genus recited in Table 6.
Description
PRIORITY
[0001] This application claims the benefit of and priority to U.S.
62/542,033, filed Aug. 7, 2017, the contents of which are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to, in part, compositions and
methods for the delivery of novel mixtures of bacterial strains
useful for decolonizing and/or eradicating infectious pathogens,
e.g., antibiotic-resistant bacteria.
DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY
[0003] The contents of the text file submitted electronically
herewith are incorporated herein by reference in their entirety: A
computer readable format copy of the Sequence Listing (filename:
FIN-003PC_ST25; date recorded: Aug. 7, 2018; file size: 6.07
MB).
BACKGROUND
[0004] Antibiotic-Resistant Bacteria (ARB) are a major health care
challenge in the US and around the world. Currently, the Centers
for Disease Control and Prevention (CDC) estimates that more than
two million people in the US develop antibiotic-resistant
infections every year, resulting in more than 23,000 deaths. The
economic burden of healthcare institution-acquired infections alone
in the US is more than $28 billion.
[0005] Many ARBs infect and/or colonize the human gastrointestinal
(GI) tract. In fact, gut colonization may be central to the problem
of ARB infections. In particular, patients who spend time in
healthcare institutions are at a high risk for GI colonization by
ARB, especially if they are immunocompromised and/or are being
treated with antibiotics and/or treated with an anti-cancer
therapy. Such treatments disrupt the gut ecosystem's natural and
critical ability to resist infection and colonization by infectious
agents, thereby creating an optimal environment for ARB infection,
growth, and colonization. These can result in ARB domination of the
gut ecosystem. GI colonization by an ARB may be asymptomatic, but
colonized patients may shed the ARB into the environment, thereby
transmitting the ARB to other patients and to healthcare workers.
Moreover, a patients whose gut is colonized and/or dominated by
antibiotic-resistant pathogens is him/herself at a higher risk for
developing life-threatening bloodstream infections (BSIs) should
the ARB translocate across the gut epithelia into the bloodstream;
s/he is also at high risk for developing catheter or
intravascular-line infections (e.g., central-line infections), for
developing chronic inflammatory diseases, for developing
meningitis, for developing pneumonia, e.g., ventilator-associated
pneumonia, for developing skin and soft tissue infections, for
developing surgical-site infections, for developing urinary tract
infections (e.g., antibiotic-resistant urinary tract infections and
catheter-associated urinary tract infections), for developing wound
infections, and for developing other well-known infections:
antibiotic-resistant infections and antibiotic-sensitive
infections.
[0006] Some healthcare institutions perform active surveillance,
including testing patients for ARB infection or colonization upon
admission and throughout a patient's stay, however, such active
surveillance can be costly; thus, few institutions can or have
implemented such surveillance. ARB-colonized or infected patients
must be put under contact precautions or isolation to prevent
transmission of the ARB to other patients and to healthcare
workers. Yet, isolation of ARB-colonized or infected patients does
nothing to reduce the patient's risk for BSI and other related
infections (as known in the art and/or as described herein), and
studies have shown isolated patients receive worse care than
non-isolated patients; additionally, isolation itself causes
emotional distress and is deleterious to the patient's outcome.
Unfortunately, there are currently no therapies for decolonizing
and/or eradicating ARB from GI-colonized patients.
[0007] Accordingly, there remains an unmet need for effective
therapies that decolonize and/or eradicate and/or reduce the load
of ARB from GI colonized patients.
SUMMARY OF THE INVENTION
[0008] The present invention is based, in part, on the discovery
that certain mixtures of commensal bacterial strains can decolonize
and/or eradicate and/or reduce the load of antibiotic-resistant
enteric pathogens in the gut. Thus, the present invention decreases
the economic burden of antibiotic resistance through reduced
patient isolation, minimizes a patient's length of stay at a
medical treatment center, reduces the number of
antibiotic-resistant infections, and lessens the need for
antibiotic prescriptions. Additionally, the present invention
diminishes the likelihood of transmission of antibiotic-resistant
bacteria to other patients and diminishes the risk of bloodstream
infection in the original patient, which is a condition with a high
mortality rate. Additionally, the present invention improves
antimicrobial stewardship by decreasing emergence and prevalence of
antibiotic-resistant infections.
[0009] In various aspects, the present invention relates to a
pharmaceutical composition comprising a bacterial mixture. The
bacterial mixture includes at least one bacterial strain comprising
a 16S rRNA sequence that is greater than about 97% identical (e.g.,
about 98%, 99%, 99.5%, and 100% identical) to the 16S rRNA sequence
of any one of the operational taxonomic units (OTUs) recited in
Table 5 and/or to the 16S rRNA sequence of any one OTU of a genus
recited in Table 6.
[0010] In various embodiments, the bacterial mixture includes at
least two bacterial strains (e.g., at least about five, ten,
twenty, thirty, forty, fifty, and one-hundred bacterial strains),
wherein a plurality of the bacterial strains comprises a 16S rRNA
sequence that is greater than about 97% identical (e.g., about 98%,
99%, 99.5%, and 100% identical) to the 16S rRNA sequence of any one
of the OTUs recited in Table 5 and/or to the 16S rRNA sequence of
any one OTU of a genus recited in Table 6. In embodiments, the
bacterial mixture includes at least two bacterial strains e.g., at
least about five, ten, twenty, thirty, forty, fifty, and
one-hundred bacterial strains), wherein each bacterial strain
comprises a 16S rRNA sequence that is greater than about 97%
identical (e.g., about 98%, 99%, 99.5%, and 100% identical) to the
16S rRNA sequence of one of the OTUs recited in Table 5 and/or to
the 16S rRNA sequence of any one OTU of a genus recited in Table
6.
[0011] In various embodiments, the bacterial mixture includes
between about five and one hundred bacterial strains (e.g., between
about ten and about seventy-five, between about fifteen and about
fifty, between about twenty and about forty-five, between about
twenty-five and about forty bacterial, and between about thirty and
about thirty-five bacterial strains), wherein a plurality of the
bacterial strains comprise a 16S rRNA sequence that is greater than
about 97% identical (e.g., about 98%, 99%, 99.5%, and 100%
identical) to the 16S rRNA sequence of any one of the OTUs recited
in Table 5 and/or to the 16S rRNA sequence of any one OTU of a
genus recited in Table 6. In embodiments, the bacterial mixture
includes between about five and about one hundred bacterial strains
(e.g., between about ten and about seventy-five, between about
fifteen and about fifty, between about twenty and about forty-five,
between about twenty-five and about forty bacterial, and between
about thirty and about thirty-five bacterial strains), wherein each
bacterial strain comprises a 16S rRNA sequence that is greater than
about 97% identical (e.g., about 98%, 99%, 99.5%, and 100%
identical) to the 16S rRNA sequence of one of the OTUs recited in
Table 5 and/or to the 16S rRNA sequence of any one OTU of a genus
recited in Table 6.
[0012] In various embodiments, the bacterial mixture comprises a
fecal microbiota preparation that comprises a donor's entire or
substantially complete microbiota. In one aspect, a fecal
microbiota preparation comprises a non-selected fecal microbiota.
In another aspect, a fecal microbiota preparation comprises an
isolated or purified population of live non-pathogenic fecal
bacteria. In a further aspect, a fecal microbiota preparation
comprises a non-selected and substantially complete fecal
microbiota preparation from a single donor. In such embodiments,
the bacterial mixture includes at least one bacterial strain
comprising a 16S rRNA sequence that is greater than about 97%
identical (e.g., about 98%, 99%, 99.5%, and 100% identical) to the
16S rRNA sequence of any one of the operational taxonomic units
(OTUs) recited in Table 5 and/or to the 16S rRNA sequence of any
one OTU of a genus recited in Table 6.
[0013] In various embodiments, at least one bacterial strain in a
bacterial mixture is a commensal bacterial strain.
[0014] In various embodiments, at least one bacterial strain in a
bacterial mixture is obtained from one or more human beings, e.g.,
a human being who is healthy and/or satisfies at least one
selection criterion.
[0015] In various embodiments, at least one bacterial strain in a
bacterial mixture is obtained from a laboratory stock or bacterial
cell bank.
[0016] In various embodiments, at least one bacterial strain in a
bacterial mixture is isolated, cultured, and/or purified from its
source material prior to forming the bacterial mixture. In various
embodiments, at least one bacterial strain in a bacterial mixture
is not isolated, cultured, and/or purified from its source material
prior to forming the bacterial mixture.
[0017] In various embodiments, at least one bacterial strain is
included in a bacterial mixture due to its ability to directly
inhibit an antibiotic-resistant bacterium (ARB), for example
through production of a secreted product and/or its capability to
directly compete with the ARB for a niche and/or for nutrients.
[0018] In various embodiments, a pharmaceutical composition further
includes a pharmaceutically acceptable excipient. In various
embodiments, a pharmaceutical composition is formulated for oral
administration and/or for delivery of the bacterial mixture to an
intestine, e.g., the small intestine and/or the large intestine
(e.g., including the cecum). In various embodiments, delivery of a
pharmaceutical composition is substantially completed prior to the
rectum. In various embodiments, a pharmaceutical composition is
formulated as a capsule, e.g., a capsule including a
delayed-release coating.
[0019] In various embodiments, a pharmaceutical composition is
formulated for vaginal administration and/or for delivery of the
bacterial mixture to the female reproductive system.
[0020] In various embodiments, a pharmaceutical composition
includes a plurality of the bacterial strains that are live,
vegetative cells, and/or lyophilized cells. A plurality of the
bacterial strains in the bacterial mixture can be spores and/or
spore-forming. In various embodiments, a plurality of the bacterial
strains (e.g., all the bacterial strains) in the bacterial mixture
can be non-pathogenic bacteria.
[0021] In various embodiments, a pharmaceutical composition is
capable of decolonizing and/or eradicating a pathogen (e.g., an
antibiotic-resistant bacterium (ARB)) in the gastrointestinal (GI)
tract of a subject, in the genitourinary tract of the subject,
and/or in the bloodstream of the subject, e.g., a human
subject.
[0022] In various aspects, the present invention relates to a
method for treating an infection by one or more pathogens. The
method includes administering to a subject (e.g., a human subject)
in need thereof an effective amount of a pharmaceutical composition
of any herein-disclosed aspect or embodiment.
[0023] In various embodiments, the one or more pathogens has
infected and/or colonized the GI tract of the subject, the
genitourinary tract of the subject, and/or the bloodstream of the
subject. In various embodiments, administering an effective amount
of the pharmaceutical composition decolonizes the one or more
pathogens and/or eradicates the one or more pathogens. In various
embodiments, the one or more pathogens treated by the method
includes one or more of Aeromonas hydrophila, Bacillus, e.g.,
Bacillus cereus, Bifidobacterium, Bordetella, Borrelia, Brucella,
Burkholderia, C. difficile, Campylobacter, e.g., Campylobacter
fetus and Campylobacter jejuni, Chlamydia, Chlamydophila,
Clostridium, e.g., Clostridium botulinum, Clostridium difficile,
and Clostridium perfringens, Corynebacterium, Coxiella, Ehrlichia,
Enterobacteriaceae, e.g., Carbapenem-resistent Enterobacteriaceae
(CRE) and Extended Spectrum Beta-Lactamase producing
Enterobacteriaceae (ESBL-E), fluoroquinolone-resistant
Enterobacteriaceae, Enterococcus, e.g., vancomycin-resistant
enterococcus spp., extended spectrum beta-lactam resistant
Enterococci (ESBL), and vancomycin-resistant Enterococci (VRE),
Escherichia, e.g., enteroaggregative Escherichia coli,
enterohemorrhagic Escherichia coli, enteroinvasive Escherichia
coli, enteropathogenic E. coli, enterotoxigenic Escherichia coli
(such as but not limited to LT and/or ST), Escherichia coli
0157:H7, and multi-drug resistant bacteria E. coli, Francisella,
Haemophilus, Helicobacter, e.g., Helicobacter pylori, Klebsiella,
e.g., Klebsiellia pneumonia and multi-drug resistant bacteria
Klebsiella, Legionella, Leptospira, Listeria, e.g., Lysteria
monocytogenes, Morganella, Mycobacterium, Mycoplasma, Neisseria,
Orientia, Plesiomonas shigelloides, Antibiotic-resistant
Proteobacteria, Proteus, Pseudomonas, Rickettsia, Salmonella, e.g.,
Salmonella paratyphi, Salmonella spp., and Salmonella typhi,
Shigella, e.g., Shigella spp., Staphylococcus, e.g., Staphylococcus
aureus and Staphylococcus spp., Streptococcus, Treponema, Vibrio,
e.g., Vibrio cholerae, Vibrio parahaemolyticus, Vibrio spp., and
Vibrio vulnificus, and Yersinia, e.g., Yersinia enterocolitica. At
least one of the one or more pathogens can be an
antibiotic-resistant bacterium (ARB), e.g., Antibiotic-resistant
Proteobacteria, Vancomycin Resistant Enterococcus (VRE), Carbapenem
Resistant Enterobacteriaceae (CRE), fluoroquinolone-resistant
Enterobacteriaceae, or Extended Spectrum Beta-Lactamase producing
Enterobacteriaceae (ESBL-E).
[0024] In various aspects, the present invention relates to a
method for preventing an infection by one or more pathogens. The
method includes administering to a subject (e.g., a human subject)
in need thereof an effective amount of a pharmaceutical composition
of any herein-disclosed aspect or embodiment.
[0025] In various embodiments, the one or more pathogens have not
yet infected and/or colonized the GI tract of the subject, the
genitourinary tract of the subject, and/or the bloodstream of the
subject. In various embodiments, administering an effective amount
of the pharmaceutical composition prevents infection and/or
colonization. In various embodiments, the one or more pathogens
have infected and/or colonized the GI tract of the subject and have
not infected and/or colonized the genitourinary tract of the
subject and/or the bloodstream of the subject. In various
embodiments, administering an effective amount of the
pharmaceutical composition prevents infection and/or colonization
of the genitourinary tract of the subject and/or the bloodstream of
the subject.
[0026] In various embodiments, the subject has been directly or
indirectly in contact with a subject having an infection or
colonization by the one or more pathogens.
[0027] In various embodiments, the one or more pathogens includes
one or more of Aeromonas hydrophila, Bacillus, e.g., Bacillus
cereus, Bifidobacterium, Bordetella, Borrelia, Brucella,
Burkholderia, C. difficile, Campylobacter, e.g., Campylobacter
fetus and Campylobacter jejuni, Chlamydia, Chlamydophila,
Clostridium, e.g., Clostridium botulinum, Clostridium difficile,
and Clostridium perfringens, Corynebacterium, Coxiella, Ehrlichia,
Enterobacteriaceae, e.g., Carbapenem-resistent Enterobacteriaceae
(CRE), fluoroquinolone-resistant Enterobacteriaceae, and Extended
Spectrum Beta-Lactamase producing Enterobacteriaceae (ESBL-E),
Enterococcus, e.g., vancomycin-resistant enterococcus spp.,
extended spectrum beta-lactam resistant Enterococci (ESBL), and
vancomycin-resistant Enterococci (VRE), Escherichia, e.g.,
enteroaggregative Escherichia coli, enterohemorrhagic Escherichia
coli, enteroinvasive Escherichia coli, enteropathogenic E. coli,
enterotoxigenic Escherichia coli (such as but not limited to LT
and/or ST), Escherichia coli O157:H7, and multi-drug resistant
bacteria E. coli, Francisella, Haemophilus, Helicobacter, e.g.,
Helicobacter pylori, Klebsiella, e.g., Klebsiellia pneumonia and
multi-drug resistant bacteria Klebsiella, Legionella, Leptospira,
Listeria, e.g., Lysteria monocytogenes, Morganella, Mycobacterium,
Mycoplasma, Neisseria, Orientia, Plesiomonas shigelloides,
Antibiotic-resistant Proteobacteria, Proteus, Pseudomonas,
Rickettsia, Salmonella, e.g., Salmonella paratyphi, Salmonella
spp., and Salmonella typhi, Shigella, e.g., Shigella spp.,
Staphylococcus, e.g., Staphylococcus aureus and Staphylococcus
spp., Streptococcus, Treponema, Vibrio, e.g., Vibrio cholerae,
Vibrio parahaemolyticus, Vibrio spp., and Vibrio vulnificus, and
Yersinia, e.g., Yersinia enterocolitica. At least one of the one or
more pathogens can be an antibiotic-resistant bacterium (ARB),
e.g., Antibiotic-resistant Proteobacteria, Vancomycin Resistant
Enterococcus (VRE), Carbapenem Resistant Enterobacteriaceae (CRE),
fluoroquinolone-resistant Enterobacteriaceae, or Extended Spectrum
Beta-Lactamase producing Enterobacteriaceae (ESBL-E).
[0028] In various embodiments, a subject in need thereof has
chronic kidney disease, cancer, and/or received an organ
transplant.
[0029] In various embodiments, a subject in need thereof has
received, is receiving, or will receive an anti-cancer therapeutic
agent and/or an anti-cancer therapy. Thus, the pharmaceutical
compositions find use in reducing, treating, or preventing a side
effect of an anti-cancer therapeutic agent and/or a side effect of
an anti-cancer therapy and/or in increasing efficacy of an
anti-cancer therapeutic agent and/or anti-cancer therapy. The
anti-cancer therapy may be surgery, radiation therapy, chemotherapy
(including hormonal therapy) and/or targeted therapy (including an
immunotherapy). In embodiments, the subject in need thereof is
suffering from a side effect of the anti-cancer therapy caused by
or related to gut dysbiosis.
[0030] An aspect of the present invention provides methods for
increasing efficacy of an anti-cancer therapeutic agent and/or
anti-cancer therapy. The method comprises administering to a
subject in need thereof an effective amount of a pharmaceutical
composition comprising a bacterial mixture as disclosed herein. The
pharmaceutical composition is administered before, after, and/or
contemporaneously with the anti-cancer therapeutic agent and/or
anti-cancer therapy.
[0031] The subject in need thereof can be in an outpatient setting,
hospitalized and/or in a long-term care facility.
[0032] In various embodiments, a subject in need thereof has or is
at risk for a bloodstream infection (BSI), catheter or
intravascular-line infections (e.g., central-line infections),
chronic inflammatory diseases, meningitis, pneumonia, e.g.,
ventilator-associated pneumonia, skin and soft tissue infections,
surgical-site infections, urinary tract infections (e.g.,
antibiotic-resistant urinary tract infections and
catheter-associated urinary tract infections), wound infections,
and/or other well-known infections: antibiotic-resistant infections
and antibiotic-sensitive infections.
[0033] Any aspect or embodiment disclosed herein can be combined
with any other aspect or embodiment as disclosed herein.
BRIEF DESCRIPTION OF THE FIGURES
[0034] FIG. 1 is a pie chart showing percentages of all operational
taxonomic units (OTUs) in the GreenGenes database that are not
found in the healthy human gut, that are found in a healthy human
gut but not included in Table 5, and that are found in a healthy
human gut and are included in Table 5.
DETAILED DESCRIPTION
[0035] The present invention is based, in part, on the discovery
that certain mixtures of commensal bacterial strains, including
non-selected or substantially complete fecal microbiota
preparations, can decolonize and/or eradicate antibiotic-resistant
enteric pathogens, e.g., caused by inappropriate broad-spectrum
antibiotic use, by a nosocomial infection, or by a previous or
current anti-cancer therapy. Thus, instead of developing new
antibiotics for decolonization, the present invention includes
novel therapeutics that treat gut dysbiosis, in part, by restoring
ARB-colonization resistance which is naturally provided by the
human microbiome. Thus, the present invention is a more effective
long-term strategy for combating antibiotic resistance than a
search for and use of new antibiotics. Moreover, the bacterial
mixtures can increase efficacy of an anti-cancer therapy, e.g., by
simulating an immune response against a cancer cell, and can
decrease the severity of a side effect or eliminate the side effect
of an anti-cancer therapy, e.g., by promoting the decolonization
and/or eradicating various pathogenic bacteria and/or
repairing/repopulating his/her gut microbiome after receiving the
anti-cancer therapy. Thus, the bacterial mixtures of the present
invention are also useful in cancer-related applications.
[0036] Mixtures of Bacterial Strains
[0037] The present invention relates to pharmaceutical compositions
of mixtures of bacterial strains that are introduced into the gut
and promote the decolonization and/or eradication of various
pathogenic bacteria; in particular antibiotic-resistant colonizing
pathogens including but not limited to: Antibiotic-resistant
Proteobacteria, Vancomycin Resistant Enterococcus (VRE), Carbapenem
Resistant Enterobacteriaceae (CRE), fluoroquinolone-resistant
Enterobacteriaceae, and Extended Spectrum Beta-Lactamase producing
Enterobacteriaceae (ESBL-E).
[0038] In embodiments, and without wishing to be bound by theory,
the mixture of bacterial strains of the present invention acts to
protect patients through one or more mechanisms. For example, a
first mechanism is direct inhibition of the pathogenic bacteria
through production of secreted products and a second mechanism is
through competition for nutrients in the gut.
[0039] The present invention is also useful in patient populations
such as chronic kidney disease on hemodialysis, oncology, and solid
organ transplant patients that are at a high risk for ARB
colonization and BSI. The present invention is also useful for
patients who are in an outpatient setting, hospitalized, and/or in
long-term care facilities.
[0040] The mixture of bacterial strains of the present invention
can be delivered to patients in a variety of ways including orally
(e.g., in a capsule), via ND/NG tube, intravaginally (e.g., as
vaginal suppository), or colonoscopically. The mixture can also be
formulated in a multitude of formulations including pure and/or
isolated cultures, both lyophilized bacteria and aqueous solutions,
spores, and as part of a broader community or mixture of bacteria
(e.g., a mixture of natural communities, including bacteria
contained in a source material, and including a substantially
complete fecal microbiota of a single healthy stool donor).
[0041] In embodiments, the present mixtures of bacterial strains
are substantially complete fecal microbiota preparations (e.g.,
from a single healthy donor). A substantially complete fecal
microbiota preparation generally comprises a full complement of
functional microorganisms found in feces of one or more healthy
humans.
[0042] In embodiments, a present mixture of bacterial strains
comprises a full complement of functional microorganisms found in
feces of one healthy human or in feces of more than one healthy
human donor. In embodiments, a present mixture of bacterial strains
comprises a full complement of functional microorganisms found in
feces of one healthy human or in feces of more than one healthy
human donor and further comprises at least one bacterial strain
comprising a 16S rRNA sequence that is greater than about 97%
identical (e.g., about 98%, 99%, 99.5%, and 100% identical) to the
16S rRNA sequence of any one of the operational taxonomic units
(OTUs) recited in Table 5 and/or to the 16S rRNA sequence of any
one OTU of a genus recited in Table 6. In other words, a bacterial
mixture comprising at least one bacterial strain in the bacterial
mixture which comprises a 16S rRNA sequence that is greater than
about 97% identical to the 16S rRNA sequence of any one OTU recited
in Table 5 or any one OTU of a genus recited in Table 6 could
further include a full complement of functional microorganisms, as
disclosed herein.
[0043] In embodiments, a present mixture of bacterial strains
comprises "less than the full complement" of functional
microorganisms found in feces of one healthy human or in feces of
more than one healthy human donor; here, at least one functional
microorganism has been omitted from the full complement. In
embodiments, a present mixture of bacterial strains comprises less
than the full complement of functional microorganisms found in
feces of one healthy human or in feces of more than one healthy
human donor and further comprises at least one bacterial strain
comprising a 16S rRNA sequence that is greater than about 97%
identical (e.g., about 98%, 99%, 99.5%, and 100% identical) to the
16S rRNA sequence of any one of the operational taxonomic units
(OTUs) recited in Table 5 and/or to the 16S rRNA sequence of any
one OTU of a genus recited in Table 6. In other words, a bacterial
mixture comprising at least one bacterial strain in the bacterial
mixture which comprises a 16S rRNA sequence that is greater than
about 97% identical to the 16S rRNA sequence of any one OTU recited
in Table 5 or any one OTU of a genus recited in Table 6 could
further include less than the full complement of functional
microorganisms, as disclosed herein.
[0044] In various embodiments, the bacterial strains of the
invention comprise bacteria isolated or purified from one or more
humans. In various embodiments, the present mixtures of bacterial
strains are isolated or purified from one or more humans. For
instance, the isolation or purification may be from feces of the
one or more humans. Further, the isolation or purification may be
from aspirates of the fluid in the GI tract or mucosal biopsies
from a site in the GI tract.
[0045] In various embodiments, the bacterial strains of the
invention are isolated or purified from its source material, i.e.,
separated from at least some of the components with which they were
associated when initially produced (e.g., when isolated from
nature, such as from feces, the bacterial strains can be isolated
from fiber and rough particulate matter; in other embodiments, when
the bacterial strains are isolated in an experimental setting
(e.g., from a laboratory stock, the bacteria can be isolated from
associated media and minerals) and/or produced, prepared, purified,
and/or manufactured by man. Bacterial strains may be separated from
at least about 10%, or about 20%, or about 30%, or about 40%, or
about 50%, or about 60%, or about 70%, or about 80%, or about 90%,
or more of the other components with which they were initially
associated. In some embodiments, bacterial strains are more than
about 80%, or about 85%, or about 90%, or about 91%, or about 92%,
or about 93%, or about 94%, or about 95%, or about 96%, or about
97%, or about 98%, or about 99%, or more than about 99% pure.
[0046] In embodiments, bacterial strains for a bacterial mixture
are directly obtained from human feces. In these embodiments, fecal
matter is collected from one or more humans and processed
ultimately until a formulation suitable for oral delivery and/or
delivery into the GI tract is prepared.
[0047] In various embodiments, fecal matter is collected from one
or more humans and processed ultimately until a formulation
suitable for vaginal delivery is prepared. An example of such
formulation is a vaginal suppository.
[0048] In other embodiments, bacterial strains for a bacterial
mixture are indirectly obtained from human feces and/or are
obtained independent of human feces (e.g., from a bacterial cell
bank or from a laboratory stock). When indirectly obtained,
bacterial strains from human feces are cultured and the bacteria
are expanded and then isolated and/or purified. The
isolated/purified bacteria can be introduced into a bacterial
mixture comprising bacterial strains directly obtained from human
feces. Alternately, a plurality of isolated/purified bacteria can
be combined into a defined bacterial mixture comprising only
bacterial strains indirectly obtained from human feces or obtained
independent of human feces.
[0049] In various embodiments, human feces are obtained from
screened, qualified donors.
[0050] In embodiments, a qualified donor provides feces having a
full complement of functional microorganisms found in feces of one
or more healthy humans, as disclosed herein.
[0051] In embodiments, a qualified donor provides feces having at
least one bacterial strain (e.g., a plurality of bacterial strains)
comprising a 16S rRNA sequence that is greater than about 97%
identical (e.g., about 98%, 99%, 99.5%, and 100% identical) to the
16S rRNA sequence of any one of the operational taxonomic units
(OTUs) recited in Table 5 and/or to the 16S rRNA sequence of any
one OTU of a genus recited in Table 6. Moreover, the qualified
donor provides feces substantially lacking bacterial strains known
to be associated with infectious diseases, as disclosed elsewhere
herein.
[0052] In embodiments of the present invention, potential donors
are screened via: (1) Initial Preliminary Screen. Prior to
enrollment, potential donors (e.g., aged about 18 to about 50)
undergo a preliminary screen comprising a subset of questions
selected from a Donor Health Questionnaire (DHQ) to assess
eligibility and/or (2) In-Person Donor Interview. If the potential
donor passes the initial preliminary screen, he/she conducts
in-person interview and clinical assessment with a healthcare
professional. As part of this interview the potential donor
completes informed consent and a donor affidavit attesting to
provide true, accurate, and complete information. The DHQ,
in-person interview, and clinical assessment determine the
potential donor's eligibility as a donor.
[0053] The DHQ and clinical assessment identify relevant criteria
which would preclude one from being a donor (e.g., temporarily and
permanently). Three categories of criteria covered by a DHQ
include: (1) Infectious risk factors, e.g., risk for factors for
multi-drug resistance organisms (MDROs); high-risk sexual
behaviors; social history, including illicit drug use; high-risk
travel history (including a 12-month exclusion if a potential donor
has traveled to a high-risk or very high-risk area, as defined by
current International SOS (ISOS) guidelines); (2) potential
microbiome-mediated conditions and general health status, e.g.,
gastrointestinal comorbidities; metabolic comorbidities;
neurological comorbidities; psychiatric comorbidities; chronic pain
syndromes; infectious diseases; autoimmune diseases; atopy, asthma
and allergies (food and other); malignancy; surgeries/other medical
history; current symptoms (including stool habits); medications
including antimicrobial therapy; diet; and family history; and (3)
pregnancy and breastfeeding status, for potential female donors. In
embodiments, the clinical assessment includes, as examples,
determination of vital signs including temperature, blood pressure,
heart rate, respiratory rate, waist circumference, and body mass
index (BMI).
[0054] In embodiments, the DHQ is analogous to that used by the Red
Cross for screening potential blood donors (with fewer or
additional questions, if desired).
[0055] Potential donors who are eligible to be donors based upon
their DHQ, in-person interview results, and clinical assessment
then undergo a series of serological, stool, and nasal swab
screens/tests. Serological, stool, and nasal swab testing/screening
are performed in conjunction with a diagnostic laboratory, e.g., a
Clinical Laboratory Improvement Amendments (CLIA)-certified
diagnostic laboratory.
[0056] Table 1 provides an overview of exemplary serological,
stool, and nasal swab screens/tests conducted as part of the donor
screening process of various embodiments. Screening/testing is
performed under conditions well-known in the art, such as, by way
of a non-limiting example: Hepatitis C may be detected by an
immunoassay (IA), Shiga may be detected by enzyme immunoassay
(EIA), and Clostridium difficile may be detected by real-time
polymerase chain reaction (RT-PCR).
TABLE-US-00001 TABLE 1 Exemplary Serological, Stool, and Nasal Swab
Screens/Tests Pathogen Serological HIV 1/2 Testing Hepatitis A
Hepatitis B Hepatitis C Treponema pallidum Strongyloides Stool
Multi-Drug Resistant VRE Testing Organisms CRE FRE ESBL Salmonella
spp Shigella spp Campylobacter spp Vibrio spp Rotavirus A
Cryptosporidium spp Shiga Giardia lamblia Adenovirus Norovirus
Clostridium difficile (e.g., a producer of Toxin B) Cryptosporidium
spp Helicobacter pylori Ova and parasites Cyclospora and Isospora
Microsporidia Bristol Stool Type assessment Nasal Swab Multi-Drug
Resistant VRE Organisms CRE FRE MRSA ESBL VRE =
Vancomycin-resistant enterococci; CRE = carbapenem-resistant
Enterobacteriaceae; ESBL = Extended-spectrum beta-lactamases; FRE =
fluoroquinolone-resistant Enterobacteriaceae.
[0057] In some embodiments, a potential donor is excluded if he/she
has a positive result in a test/screen for an infectious disease,
e.g., caused by one of the pathogens listed in Table 1. In some
embodiments, a potential donor who tests positive for HIV-1/2,
Hepatitis B, or Hepatitis C is indefinitely excluded from
donating.
[0058] In some embodiments, a potential donor who tests positive
for Hepatitis A, Treponema pallidum, or Strongyloides is deferred
from donating until eight weeks after a successful treatment has
been completed, symptoms have resolved, and no recurrence of
symptoms have occurred.
[0059] In some embodiments, a potential donor who tests positive
for Adenovirus, Campylobacter spp, Clostridium difficile toxin B,
Cryptosporidium spp, Cyclospora and Isospora, Giardia lamblia,
Proteus, Morganella, Helicobacter pylori, Microsporidia, Norovirus,
Ova and parasites, Salmonella spp, Shiga, Shigella spp, or Vibrio
spp, is immediately placed on hold and deferred for eight weeks
from symptom resolution, completion of treatment, and no
recurrence. Screened donors deferred for eight weeks from symptom
resolution, completion of treatment, and no recurrence due to any
of the above may undergo a full repeat screen to evaluate for
inclusion.
[0060] In some embodiments, a potential donor who tests positive
for rotavirus is placed immediately on donation hold and undergoes
repeat confirmatory testing. If confirmed positive, these donors
are ineligible for donation for eight weeks. Screened donors
deferred for eight weeks due to rotavirus may undergo a full repeat
screen to evaluate for inclusion.
[0061] In some embodiments, a potential donor who tests positive
for a Multi-Drug Resistant Organism (MDROs), e.g.,
Vancomycin-resistant Enterococcus (VRE), Carbapenem-resistant
enterobacteriaceae (CRE), fluoroquinolone-resistant
Enterobacteriaceae (FRE), and Extended-spectrum beta-lactamase
(ESBL) is immediately placed on hold and deferred for eight weeks
after successful treatment/decolonization with no symptoms or
recurrence. Screened donors deferred for eight weeks after
successful treatment/decolonization with no symptoms or recurrence
due to any of the above may undergo a full repeat screen to
evaluate for inclusion.
[0062] In some embodiments, a potential donor who tests positive
for Methicillin-resistant Staphylococcus aureus (MRSA) is
immediately placed on hold and deferred for eight weeks after
successful treatment/decolonization with no symptoms or recurrence.
Screened donors deferred for eight weeks after successful
treatment/decolonization with no symptoms or recurrence due to any
of the above may undergo a full repeat screen to evaluate for
inclusion.
[0063] In some embodiments, potential donors may submit samples for
additional screening which may include assays for Liver Function
Panel, Alanine Aminotransferase (ALT), Aspartate Aminotransferase
(AST), Alkaline Phosphatase (ALP), Albumin, Bilirubin (Total,
direct, or indirect), and Complete Blood Count (CBC) with
Differential. Donors whose results from these Additional Screening
assays are outside the bounds of normal (see, e.g., Table 2) are
ineligible to donate stool.
TABLE-US-00002 TABLE 2 Exemplary Low and High limit for Complete
Blood Count (CBC) and Hepatic Function Panel (HFP) Test Category
Low High Units CBC WBC 3.8 10.8 .times.10.sup.3/.mu.L CBC RBC 4.20
5.80 .times.10.sup.6/.mu.L CBC Hemoglobin 13.2 17.1 g/dL CBC
Hematocrit 38.5 50.0 % CBC MCV 80 100 fL CBC MCH 27.0 33.0 pg CBC
MCHC 32.0 36.0 g/dL CBC RDW 11 15 % CBC Platelets 140 400
.times.10.sup.3/.mu.L CBC MPV 7.5 11.5 fL CBC Absolute Neutrophils
1500 7800 cells/.mu.L CBC Absolute Lymphocytes 850 3900 cells/.mu.L
CBC Absolute Monocytes 200 950 cells/.mu.L CBC Absolute Eosinophils
15 500 cells/.mu.L CBC Absolute Basophils 0 200 cells/.mu.L HFP
Protein, Total, Serum 6.1 8.1 g/dL HFP Albumin, Serum 3.6 5.1 g/dL
HFP Bilirubin, Total 0.2 1.2 mg/dL HFP Bilirubin, Direct 0.00 0.20
mg/dL HFP Bilirubin, Indirect 0.2 1.2 mg/dL HFP Alkaline
Phosphatase, Serum 40 115 U/L HFP AST (SGOT) 10 40 U/L HFP ALT
(SGPT) 9 46 U/L
[0064] If the cause of abnormal assay results is found to be either
infectious or may otherwise compromise the health of the donor or
an FMT recipient, that donor may be excluded from donating stool
for clinical use. If the cause of the abnormal reading is
determined to be not clinically significant and to pose no threat
to an FMT recipient, as examples, the result is an incidental
artifact or due to Gilbert's syndrome, then the donor may be
considered for enrollment/re-enrollment.
[0065] Other screens or tests may also be used to exclude or
include potential donors.
[0066] In some embodiments, a potential donor may be positive for
one or both of Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV).
There have not been any reported cases of CMV or EBV infection
among those who have received FMT from adult donors (Wang et al.
2016), including a large series of immunocompromised patients
(Kelly et al. 2014) and solid organ transplant patients (Fischer et
al. 2017).
[0067] In some embodiments, a potential donor may be positive for
Listeria monocytogenes. In embodiments, donated material and/or
serological samples are not tested for L. monocytogenes unless the
donor is symptomatic for a L. monocytogenes infection.
[0068] In some embodiments, before or after a stool donation event,
the pre-screened donor again completes a DHQ. A donor's eligibility
will be further evaluated should he/she have any positive responses
in this questionnaire. If the donor's responses indicate any
changes in health status that involve an exclusion criterion, the
donated material is discarded. When the donor's DHQ results do not
indicate exclusion, the container and the stool material contained
therein is processed.
[0069] In some embodiments, a donor may complete an in-person
clinical health check around the time of a stool donation to ensure
the donor's health. If the donor does not have good/optimal health,
the donated material may be discarded.
[0070] In some embodiments, a donor is generally of good health and
has microbiota consistent with such good health. Often, the donor
has not been administered an antibiotic compound within a certain
period prior to a stool donation.
[0071] In some embodiments, the donor does not have irritable bowel
disease (e.g., Crohn's disease and ulcerative colitis), irritable
bowel syndrome, celiac disease, colorectal cancer, or a family
history of these diseases.
[0072] In some embodiments, a donor is selected for the presence of
certain genera and/or species that provide increased efficacy of
therapeutic compositions containing these genera or species. In
some embodiments, a preferred donor donates stool material having a
relatively high concentration of spores. In some embodiments, a
preferred donor donates stool material comprising spores having
increased efficacy.
[0073] In some embodiments, a sample of a donated stool material or
a donated stool may be used for Additional Screening. Additional
Screening may include assays for Liver Function Panel, Alanine
Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline
Phosphatase (ALP), Albumin, Bilirubin (Total, direct, indirect),
and Complete Blood Count (CBC) with Differential. Donors whose
results from these Additional Screening assays are outside the
bounds of normal (see, e.g., Table 2) the donated material may be
discarded.
[0074] Other screens or tests may also be used to temporarily or
permanently exclude donors.
[0075] In some embodiments, a donor who tests positive for
Hepatitis A, Treponema pallidum, or Strongyloides is deferred from
donating until eight weeks after a successful treatment has been
completed, symptoms have resolved, and no recurrence of symptoms
have occurred. Impacted donated material will be destroyed.
Screened donors deferred for eight weeks from symptom resolution,
completion of treatment, and no recurrence due to any of the above
may undergo a full repeat screen to evaluate his/her return as a
donor.
[0076] In some embodiments, a donor who tests positive for
Adenovirus, Campylobacter spp, Clostridium difficile toxin B,
Cryptosporidium spp, Cyclospora and Isospora, Giardia lamblia,
Proteus, Morganella, Helicobacter pylori, Microsporidia, Norovirus,
Ova and parasites, Salmonella spp, Shiga, Shigella spp, or Vibrio
spp, is immediately placed on hold and deferred for eight weeks
from symptom resolution, completion of treatment, and no
recurrence. Impacted donated material will be discarded. Screened
donors deferred for eight weeks from symptom resolution, completion
of treatment, and no recurrence due to any of the above may undergo
a full repeat screen to evaluate his/her return as a donor.
[0077] In some embodiments, a donor who tests positive for
rotavirus will be placed immediately on donation hold and have
repeat confirmatory testing performed. If confirmed positive, these
donors will have their donated material discarded and will be
ineligible for donation for eight weeks. Screened donors deferred
for eight weeks due to rotavirus may undergo a full repeat screen
to evaluate his/her return as a donor.
[0078] A donor who tests positive for a Multi-Drug Resistant
Organism (MDROs), e.g., Vancomycin-resistant Enterococcus (VRE),
Carbapenem-resistant enterobacteriaceae (CRE),
fluoroquinolone-resistant Enterobacteriaceae (FRE) and
Extended-spectrum beta-lactamase (ESBL) is immediately placed on
hold and deferred for eight weeks after successful
treatment/decolonization with no symptoms or recurrence. Impacted
donated material will be discarded. Screened donors deferred for
eight weeks after successful treatment/decolonization with no
symptoms or recurrence due to any of the above may undergo a full
repeat screen to evaluate his/her return as a donor.
[0079] In some embodiments, a donor who tests positive for
Methicillin-resistant Staphylococcus aureus (MRSA) is immediately
placed on hold and deferred for eight weeks after successful
treatment/decolonization with no symptoms or recurrence. Impacted
donated material will be discarded. Screened donors deferred for
eight weeks after successful treatment/decolonization with no
symptoms or recurrence due to any of the above may undergo a full
repeat screen to evaluate his/her return as a donor.
[0080] In some embodiments, a donor may be positive for one or both
of Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). There have
not been any reported cases of CMV or EBV infection among those who
have received FMT from adult donors (Wang et al., 2016), including
a large series of immunocompromised patients (Kelly et al., 2014)
and solid organ transplant patients (Fischer et al., 2017).
[0081] In some embodiments, a donor undergoes a blood test about
twenty-one days, e.g., two weeks to a month, or longer, after
his/her last donation to account for HIV seroconversion.
[0082] In some embodiments, a donor may be positive for Listeria
monocytogenes. In embodiments, donated material and/or serological
samples are not tested for L. monocytogenes unless the donor is
symptomatic for a L. monocytogenes infection.
[0083] In embodiments, processing of a donated material begins
within six hours of passage of stool material. Elapsed time prior
to stool processing may be noted.
[0084] In some embodiments, donated material will be assessed using
the Bristol stool scale and/or for hematochezia, melena, mucus,
and/or steatorrhea. Collection of samples from the donated material
may occur within the biosafety cabinet.
[0085] Stool below Bristol Type 3 and stool above Bristol Type 5 is
discarded.
[0086] Stool exhibiting signs of hematochezia, melena, mucus,
and/or steatorrhea is discarded.
[0087] In some embodiments, donated material is quarantined (i.e.,
not included in a drug substance and/or not included in a drug
product) for a "collection window" of about sixty days, e.g.,
thirty to ninety days, and until the donor has passed a second DHQ,
a second in-person clinical assessment, and/or a second set of
serological, stool, and/or nasal swab tests (as described above).
See, Table 3.
TABLE-US-00003 TABLE 3 Donor Screening/Testing Testing Time Points
Start of End of collection collection Parameter Acceptance Criteria
window window Questionnaire & Interview Pass x x Serological
Negative for a panel of Infectious Diseases x x Stool Negative for
a panel of Viruses, Enteric x x Pathogens, Parasites, etc. MDRO
Negative for a panel of Multi-Drug x x Resistant Organisms
Additional Screening "Normal" for a Liver Function panel and x x
Complete Blood Count & Differential .sup.b Donor Health
Questionnaire No issues noted that involve Exclusion x x (DHQ)
completed at Delivery .sup.a Criteria .sup.a In addition to the
DHQ, if a donor experiences any abnormal symptoms, including a
change in bowel habits or change in other relevant clinical factors
(e.g., medicines and medical history) donors should notify to the
donation facility immediately. A full health assessment is
conducted and if symptoms would lead to stool that may impact the
health of an FMT recipient, donation is suspended until an
examination of the underlying symptoms is initiated by clinical
assessment and/or diagnostic tests on stool and/or blood. The
impacted material may be discarded. In the event of transient,
self-limiting, mild symptoms, donors may be eligible when symptoms
resolve. .sup.b See, Table 2
TABLE-US-00004 TABLE 4 Physical Testing Conducted on Donated
Material Parameter Acceptance Criteria Justification Bristol
Bristol Stool Type Bristol Stool Type of 2, 3, 4, and 5 are
considered Stool Type must be healthy. Types above that range (i.e.
Type 6 and 7) Type 3, 4, or 5 indicate diarrhea; these Stool Types
are not processed. Stool with a Bristol Stool Type 1 or 2, which
indicates constipation, may be too rigid or dense for readily
processing; these Stool Types are not processed. Screening
Hematochezia Visually The presence of fresh blood in stool
indicates of Stool for Absent lower gastrointestinal pathology
(e.g., Hematochezia diverticulosis and inflammatory bowel disease)
or, less commonly, a brisk upper gastrointestinal bleed. Stool with
hematochezia is not processed. Screening Melena Visually Absent The
presence of melena in stool indicates upper of Stool for
gastrointestinal bleeding (e.g., peptic ulcer Melena disease,
gastritis, and esophageal varices). Stool with melena is not
processed. Screening Mucus Visually Absent Although small amounts
of mucus are normal, the of Stool for presence of mucus in stool
potentially indicates Mucus gastrointestinal pathology (e.g.,
inflammatory bowel disease and malignancy). Stool with mucus is
processed. Screening Steatorrhea Visually The presence of
steatorrhea in stool indicates fat of Stool for Absent
malabsorption (e.g., pancreatic insufficiency). Stool Steatorrhea
with steatorrhea is not processed.
[0088] In some embodiments, the viability of the microbiota of the
donated stool may be confirmed by culturing a sample of the donated
stool, an otherwise purified form of the donated stool, a filtrate,
a homogenized product, a thawed-frozen intermediate, a pooled
material, and/or a drug substance. Methods for culturing microbiota
from stool or from stool-derived products are well-known in the
art. In some embodiments, microbiota are cultured using the Center
for Disease Control (CDC) plate, commonly referred to as "CDC
Anaerobe 5% Sheep Blood Agar plate, which allows for the isolation
and cultivation of fastidious and slow-growing obligatory anaerobic
bacteria, the Bacteroides Bile Esculin Agar (BBE) plate, which is a
specific indicator species media for Bacteroides, or GIFU Anaerobic
Medium Agar (GM). In some embodiments, the number of viable,
culturable cells within the stool or stool-derived products may be
confirmed by the presence of a colony forming unit (CFU) counts,
e.g., by the Drop Plate CFU Assay. The diversity of the living
microbes in the stool or from stool-derived products may be
assayed. The mix of microbes present, or diversity of microbes, is
a further measure of the quality of the donated stool and the drug
substance.
[0089] In some embodiments, the viability of the microbiota of the
donated stool may be confirmed by PMAseq; Chu et al., "Using
Propodium Monoazide Sequencing (PMA-Seq) to Develop Data-Driven
Best Practices in Fecal Microbiota Transplantations." Open Forum
Infect Dis. Oxford University Press; 2015)]. Briefly, this approach
provides a high-throughput, culture-independent measure of cell
viability.
[0090] In some embodiments, the bacteria are live, vegetative
cells. In some embodiments, the bacteria are capable of forming
spores. In some embodiments, the bacteria are in the form of
spores, e.g., viable spores. In some embodiments, the mixtures of
bacterial strains as described herein comprise live, vegetative
cells and spores. In some embodiments, the mixture of bacterial
strains as described herein is substantially free of live,
vegetative cells. In some embodiments, the mixture of bacterial
strains as described herein is substantially free of spores. In
some embodiments, the bacterial strains are in the form of live,
vegetative cells. In some embodiments, the bacterial strains are in
the form of spores. In some embodiments, the bacterial strains are
in the form of lyophilized cells. In some embodiments, the
bacterial mixture comprises one or more of live, vegetative cells;
spores; and lyophilized cells.
[0091] In some embodiments, the bacterial strains are
non-pathogenic. For instance, in some embodiments, the bacterial
strains are substantially free of organisms or entities which are
capable of causing or affecting a disease, disorder or condition of
a host organism containing the organism or entity. Illustrative
pathogenic bacteria are provided elsewhere herein.
[0092] In various embodiments, the mixture of bacterial strains
includes one or more non-pathogenic bacterial strains that are able
to engraft in a patient's GI tract. In some embodiments, the
mixture of bacterial strains includes one or more non-pathogenic
bacterial strains that are able to colonize a patient's mucosal
barrier. In some embodiments, the mixture of bacterial strains
includes one or more bacterial strains that preserve and/or enhance
mucosal barrier integrity and function in a patient. In various
embodiments, the mixture of bacterial strains includes one or more
bacterial strains that decolonize pathogenic infectious agents. In
some embodiments, the mixture of bacterial strains includes one or
more bacterial strains that compete with pathogenic infectious
agents for resources (e.g., niche and/or nutrients). In another
embodiment, the mixture of bacterial strains includes one or more
bacterial strains that enhance production of one or more of
butyrate, acetate, and propionate in the gut. In various
embodiments, the mixture of bacterial strains includes one or more
bacterial strains that supplement SOFA production in the gut. In
various embodiments, the mixture of bacterial strains induces
proliferation and/or accumulation of Foxp3.sup.+ cells, e.g.,
regulatory T cells (T.sub.regs) in the mucosal lining of the gut.
In various embodiments, the mixture of bacterial strains induces
proliferation and/or accumulation of interleukin-10 (IL-10) in the
gut. In various embodiments, the mixture of bacterial strains
reduces proliferation and/or accumulation of interleukin-12
(IL-12), interleukin-4 (IL-4), and/or and gamma interferon (IFN
.gamma.) in the gut.
[0093] Without wishing to be bound by theory, treatment of the gut
microbiome with antibiotics can result in a reduction of butyrate
levels in the gut. Butyrate serves as the primary energy source of
colonocytes and with decreased butyrate levels, colonocytes switch
to anaerobic/fermentative growth. Because this growth does not
utilize oxygen, the gut barrier becomes increasingly oxygenated.
Butyrate also normally inhibits nitric oxide synthase, so in the
absence of normal butyrate levels, the concentration of
host-derived nitrate in the gut increases. Enterobacteriaceae are
often opportunistic pathogens, and blooms of these bacteria are a
sign of dysbiosis and inflammation. Members of Enterobacteriaceae
can use both nitrate and oxygen as electron acceptors during
respiration. Therefore, antibiotic treatment can result in
decreased butyrate production, leading to increased oxygen and
nitrate content in the gut, which gives potentially pathogen
facultative anaerobes like Enterobacteriaceae a growth advantage,
resulting in an Enterobacteriaceae bloom.
[0094] In various embodiments, the present mixture of bacterial
strains provides both systemic anti-inflammatory and
immunoregulatory effects.
[0095] In various embodiments, the present mixture of bacterial
strains includes one or more isolated or purified bacterial strains
that individually or when together in a mixture have a cytotoxic or
cytostatic effect on a pathogenic bacterium, as described elsewhere
herein, e.g., can eradicate and/or decolonize pathogenic infectious
bacteria. In various embodiments, the present mixture of bacterial
strains exerts an inhibitory effect on a pathogenic bacterium
present in or entering into the GI tract of a patient. In various
embodiments, the present mixture of bacterial strains augments
growth of at least one type of bacteria not detectably present in a
patient's GI tract prior to administration. In various embodiments,
the present mixture of bacterial strains includes one or more
isolated or purified bacterial strains that interact
synergistically to have a cytotoxic or cytostatic effect on a
pathogenic bacterium.
[0096] Illustrative pathogenic bacteria include C. difficile,
Salmonella spp., enteropathogenic E. coli, multi-drug resistant
bacteria such as Klebsiella, and E. coli, Carbapenem-resistent
Enterobacteriaceae (CRE), extended spectrum beta-lactam resistant
Enterococci (ESBL), fluoroquinolone-resistant Enterobacteriaceae,
and vancomycin-resistant Enterococci (VRE). Further illustrative
bacteria include Yersinia, Vibrio, Treponema, Streptococcus,
Staphylococcus, Shigella, Salmonella, Rickettsia, Orientia,
Pseudomonas, Neisseria, Mycoplasma, Mycobacterium, Listeria,
Leptospira, Legionella, Klebsiella, Helicobacter, Haemophilus,
Francisella, Escherichia, Ehrlichia, Enterococcus, Coxiella,
Corynebacterium, Clostridium, Chlamydia, Chlamydophila,
Campylobacter, Burkholderia, Brucella, Borrelia, Bordetella,
Bifidobacterium, Bacillus, Proteus, Morganella, multi-drug
resistant bacteria, extended spectrum beta-lactam resistant
Enterococci (ESBL), Carbapenem-resistent Enterobacteriaceae (CRE),
fluoroquinolone-resistant Enterobacteriaceae, and
vancomycin-resistant Enterococci (VRE). Illustrative pathogenic
bacteria include Aeromonas hydrophila, Campylobacter fetus,
Plesiomonas shigelloides, Bacillus cereus, Campylobacter jejuni,
Clostridium botulinum, Clostridium difficile, Clostridium
perfringens, enteroaggregative Escherichia coli, enterohemorrhagic
Escherichia coli, enteroinvasive Escherichia coli, enterotoxigenic
Escherichia coli (such as, but not limited to, LT and/or ST),
Escherichia coli O157:H7, Helicobacter pylori, Klebsiellia
pneumonia, Lysteria monocytogenes, Plesiomonas shigelloides,
Salmonella spp., Salmonella typhi, Salmonella paratyphi, Shigella
spp., Staphylococcus spp., Staphylococcus aureus,
vancomycin-resistant enterococcus spp., Vibrio spp., Vibrio
cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, and Yersinia
enterocolitica. Specifically-relevant pathogenic bacteria include
Antibiotic-resistant Proteobacteria, Vancomycin Resistant
Enterococcus (VRE), Carbapenem Resistant Enterobacteriaceae (CRE),
fluoroquinolone-resistant Enterobacteriaceae, and Extended Spectrum
Beta-Lactamase producing Enterobacteriaceae (ESBL-E).
[0097] In various embodiments, a bacterial strain is included in
the pharmaceutical composition of the invention based upon its 16S
rRNA sequence identity. In an embodiment, the pharmaceutical
composition of the invention comprises one or more bacterial
strains having a 16S rRNA sequence that is at least about 80%
identical to the 16S rRNA sequence of any one of the operational
taxonomic units (OTUs) provided in Table 5 or Table 6. For example,
the pharmaceutical composition may comprise one or more bacterial
strains having a 16S rRNA sequence that is at least about 80%,
about 81%, about 82%, about 83%, about 84%, about 85%, about 86%,
about 87%, about 88%, about 89%, about 90%, about 91%, about 92%,
about 93%, about 94%, about 95%, about 96%, about 97%, about 98%,
about 99%, or about 100% identical with the 16S rRNA sequence of
any one of the operational taxonomic units provided in Table 5 or
Table 6. In an embodiment, the pharmaceutical composition may
comprise one or more bacterial strains having a 16S rRNA sequence
that is at least about 97%, at least about 98%, at least about 99%,
or about 100% identical with the 16S rRNA sequence of any one of
the operational taxonomic units provided in Table 5 or Table 6.
[0098] In various embodiments, the pharmaceutical composition of
the invention comprises a bacterial mixture of at least about 50
different bacterial strains, or at least about 49 different
bacterial strains, or at least about 48 different bacterial
strains, or at least about 47 different bacterial strains, or at
least about 46 different bacterial strains, or at least about 45
different bacterial strains, or at least about 44 different
bacterial strains, or at least about 43 different bacterial
strains, or at least about 42 different bacterial strains, or at
least about 41 different bacterial strains, or at least about 40
different bacterial strains, or at least about 39 bacterial
strains, or at least about 38 bacterial strains, or at least about
37 bacterial strains, or at least about 36 bacterial strains, or at
least about 35 bacterial strains, or at least about 34 bacterial
strains, or at least about 33 bacterial strains, or at least about
32 bacterial strains, or at least about 31 bacterial strains, or at
least about 30 bacterial strains, or at least about 29 bacterial
strains, or at least about 28 bacterial strains, or at least about
27 bacterial strains, or at least about 26 bacterial strains, or at
least about 25 bacterial strains, or at least about 24 bacterial
strains, or at least about 23 bacterial strains, or at least about
22 bacterial strains, or at least about 21 bacterial strains, or at
least about 20 bacterial strains, or at least about 19 bacterial
strains, or at least about 18 bacterial strains, or at least about
17 bacterial strains, or at least about 16 bacterial strains, or at
least about 15 bacterial strains, or at least about 14 bacterial
strains, or at least about 13 bacterial strains, or at least about
12 bacterial strains, or at least about 11 bacterial strains, or at
least about 10 bacterial strains, or at least about 9 bacterial
strains, or at least about 8 bacterial strains, or at least about 7
bacterial strains, or at least about 6 bacterial strains, or at
least about 5 bacterial strains, or at least about 4 bacterial
strains, or at least about 3 bacterial strains, or at least about 2
bacterial strains, or about 1 bacterial strain with reference to
Table 5 or Table 6, e.g., as listed in Table 5 or Table 6 or having
a 16S rRNA sequence that is, as examples, at least about 95%, at
least about 96%, at least about 97%, at least about 98%, at least
about 99%, or about 100% identical with the 16S rRNA sequence of
any one of the strains listed in Table 5 or Table 6.
[0099] In various embodiments, the pharmaceutical composition of
the invention comprises a bacterial mixture of about 50 or fewer
different bacterial strains as described herein (e.g., with
reference to Table 5 or Table 6).
[0100] In some embodiments, the pharmaceutical composition of the
invention comprises greater than about 2, greater than about 5, or
greater than about 10, or greater than about 15, or greater than
about 20, or greater than about 25, or greater than about 30, or
greater than about 35, or greater than about 40, or greater than
about 45, or greater than about 50, greater than about 75, or
greater than about 100 different bacterial strains as described
herein (e.g., with reference to Table 5 or Table 6).
[0101] In some embodiments, the pharmaceutical composition of the
invention comprises less than about 5, or less than about 10, or
less than about 15, or less than about 20, or less than about 25,
or less than about 30, or less than about 35, or less than about
40, or less than about 45, or less than about 50 different
bacterial strains as described herein (e.g., with reference to
Table 5 or Table 6).
[0102] In some embodiments, the pharmaceutical composition of the
invention comprises about 10 to about 50 different bacterial
strains as described herein (e.g., with reference to Table 5 or
Table 6), including about 10 to about 45, or about 10 to about 40,
or about 10 to about 30, or about 10 to about 20, or about 10 to
about 15 different bacterial strains.
[0103] In some embodiments, the pharmaceutical composition of the
invention comprises about 10 to about 20 different bacterial
strains as described herein (e.g., with reference to Table 5 or
Table 6).
[0104] In various embodiments, the mixtures of bacterial strains
are selected from any of the bacterial strains listed in Table 5 or
Table 6 below or the bacterial strains having a 16S rRNA sequence
that is, as examples, at least about 95%, at least about 96%, at
least about 97%, at least about 98%, at least about 99%, or about
100% identical with the 16S rRNA sequence of any one of the strains
listed in Table 5 or Table 6 below.
[0105] In embodiments, the mixtures of bacterial strains are
substantially complete or non-selected fecal microbiota
preparations (e.g., from a single healthy stool donor), which
generally comprises a full complement of functional microorganisms
found in feces of one or more healthy humans. Such mixtures of
bacterial strains may further comprise one or more strains listed
in Table 5 or Table 6 below and/or one or more strains having a 16S
rRNA sequence that is at least about 95% identical with the 16S
rRNA sequence of any one of the strains listed in Table 5 or Table
6 below.
[0106] Table 5 lists OTUs by their GreenGenes identification number
and the Latin taxonomic name associated with each OTU. [0107]
Columns: [0108] A--GreenGenes ID for OTU [0109] B--The number of
stool donors that OTU is present in [0110] C--The fraction of all
stool donors that OTU is present in [0111] D--Taxonomy for that OTU
[0112] E--SEQ ID NO associated with the OTU
TABLE-US-00005 [0112] TABLE 5 Exemplary OTUs Useful in the Present
Invention A.sup.1 B C D.sup.2 E 9710 6 0.095238095 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1 f:
Enterobacteriaceae; g:; s: 14157 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
2 g:; s: 14159 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: [Mogibacteriaceae]; 3 g:; s: 15286
1 0.015873016 k: Bacteria; p: Firmicutes; c: Bacilli; o:
Lactobacillales; f: Enterococcaceae; 4 g: Enterococcus; s: 16036 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 5 g: Ruminococcus; s:
flavefaciens 16054 33 0.523809524 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 6 g:
Ruminococcus; s: callidus 17311 9 0.142857143 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 7 g:; s: 20321 5 0.079365079 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 8 f:
Enterobacteriaceae; g: Erwinia; s: 31319 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
9 g: Clostridium; s: subterminale 34789 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 10 g:; s: 35260 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 11 g:; s: 36792 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
12 g:; s: 41229 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 13 f: Alcaligenaceae; g:
Sutterella; s: 42839 51 0.80952381 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 14 g:
Ruminococcus; s: 43950 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 15 g:
Oscillospira; s: 44827 7 0.111111111 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 16 g:
Ruminococcus; s: flavefaciens 45074 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 17
g: Clostridium; s: 45363 44 0.698412698 k: Bacteria; p: Firmicutes;
c: Erysipelotrichi; o: Erysipelotrichales; 18 f:
Erysipelotrichaceae; g: Clostridium; s: cocleatum 48444 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 19 g: Ruminococcus; s: 66188 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 20 g: Oscillospira; s: 68841 10
0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 21 g: Lachnospira; s: 72481 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 22 g: Coprococcus; s: 73753 52
0.825396825 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 23 f: [Odoribacteraceae]; g: Odoribacter; s: 91359 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 24 g: Lachnospira; s: 91557 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 25 f: Enterobacteriaceae; g:; s: 91962 4
0.063492063 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 26 f: Enterobacteriaceae; g:; s: 100506 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 27 g: Coprococcus; s: 105538 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 28 g: Clostridium; s: 105964 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 29 g: Ruminococcus; s:
flavefaciens 107044 16 0.253968254 k: Bacteria; p: Bacteroidetes;
c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 30 g:
Alistipes; s: massiliensis 110192 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 31
g: Oscillospira; s: 110458 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 32 g:; s: 110562 14 0.222222222 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
33 g: Ruminococcus; s: 112720 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
34 g:; s: 112891 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 35 f: Alcaligenaceae; g:
Sutterella; s: 113003 13 0.206349206 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 36 g:
Ruminococcus; s: 114462 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 37 f:
Enterobacteriaceae; g:; s: 115035 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 38
g: Oscillospira; s: 119010 6 0.095238095 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 39 f:
Enterobacteriaceae; g: Xenorhabdus; s: bovienii 122656 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 40 g:; s: 129401 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 41 g: Oscillospira; s: 132784 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 42 g: Phascolarctobacterium; s:
132991 45 0.714285714 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 43 g: Faecalibacterium; s:
prausnitzii 136127 9 0.142857143 k: Bacteria; p: Actinobacteria; c:
Coriobacteriia; o: Coriobacteriales; 44 f: Coriobacteriaceae; g:;
s: 136789 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Ruminococcaceae; 45 g: Ruminococcus; s: 137353
13 0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 46 g: Coprococcus; s: 141145 2
0.031746032 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 47 f: Enterobacteriaceae; g:; s: 145236 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 48 g:; s: 145856 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 49 g:; s: 145887 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 50 g:; s: 147071 54
0.857142857 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 51 f: Coriobacteriaceae; g: Collinsella; s:
147195 10 0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 52 g: Coprococcus; s: 147484 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 53 g:; s: 148620 48
0.761904762 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 54 f: Enterobacteriaceae; g: Erwinia; s:
148925 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 55 g: Ruminococcus; s: 149588 16
0.253968254 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 56 f: Enterobacteriaceae; g: Erwinia; s:
157162 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 57 g: Oscillospira; s: 157224 11
0.174603175 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 58 g: Faecalibacterium; s:
prausnitzii 157573 1 0.015873016 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 59 g:; s: 157772
22 0.349206349 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 60 g: Oscillospira; s: 158045 33
0.523809524 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 61 g: Faecalibacterium; s:
prausnitzii 158113 3 0.047619048 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 62 f: Alcaligenaceae; g:
Sutterella; s: 158183 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 63 g:
Oscillospira; s: 158297 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 64 g:
Ruminococcus; s: 158722 11 0.174603175 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 65 g:
Oscillospira; s: 160750 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 66 g:
Coprococcus; s: 161762 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 67 g:
Ruminococcus; s: 162215 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 68 f:
Enterobacteriaceae; g:; s: 162660 20 0.317460317 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 69
g: Ruminococcus; s: 163243 10 0.158730159 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 70
g: Ruminococcus; s: 163421 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 71 f:
Enterobacteriaceae; g: Citrobacter; s: 165046 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 72 g: Oscillospira; s: 165924 55 0.873015873 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 73 g: Faecalibacterium; s: prausnitzii 166156 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 74 g: Coprococcus; s: 166164 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 75 g: Ruminococcus; s: 166226 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 76 g: Oscillospira; s: 166908 59
0.936507937 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 77 f: Enterobacteriaceae; g:; s: 166913 43
0.682539683 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 78 169031 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Veillonellaceae; 79 g: Phascolarctobacterium; s: 169182 3
0.047619048 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 80 f: Enterobacteriaceae; g:; s: 171184 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 81 171437 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 82 171772 12 0.19047619 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
g:; s: 83
173103 7 0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 84 173135 13 0.206349206
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 85 g: Faecalibacterium; s: prausnitzii 173654 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 86 f: Enterobacteriaceae; g:; s: 173726 28
0.444444444 k: Bacteria; p: Proteobacteria; c: Betaproteobacteria;
o: Burkholderiales; 87 f: Alcaligenaceae; g: Sutterella; s: 173792
3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 88 g: Ruminococcus; s: 173969 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 89 g: Coprococcus; s: 173986 9
0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 90 g: Faecalibacterium; s:
prausnitzii 174045 42 0.666666667 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 91 g:
Coprococcus; s: 174142 3 0.047619048 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 92 f:
Coriobacteriaceae; g:; s: 174233 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 93 174403 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 94 g:
Faecalibacterium; s: prausnitzii 174439 43 0.682539683 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
95 g: Faecalibacterium; s: prausnitzii 174497 9 0.142857143 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 96 g: Clostridium; s: 174516 7 0.111111111 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 97 g: Clostridium; s: 174607 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 98 g: Ruminococcus; s: 174614 48 0.761904762 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 99 g: Ruminococcus; s: 174625 9 0.142857143 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 100 g: Coprococcus; s: 174654 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 101 g: Ruminococcus; s: bromii 174688 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 102 g: Clostridium; s: 174712 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 103 g: Ruminococcus; s: 174755
12 0.19047619 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 104 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 174960 7 0.111111111 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 105 174974
12 0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 106 g: Lachnospira; s: 175037 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 107 g:; s: 175375 2
0.031746032 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 108 g:; s: 175397 59 0.936507937
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 109 g: Coprococcus; s: 175438 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 110 g: Coprococcus; s: 175508 46 0.73015873 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 111 f: Coriobacteriaceae; g:; s: 175560 63 1 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 112 g: Faecalibacterium; s: prausnitzii 175846 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 113 g: Coprococcus; s: 175883 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 114 g: Coprococcus; s: 175898 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 115 g: Oscillospira; s: 175922 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 116 g: Oscillospira; s: 176094 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 117 g: Ruminococcus; s: 176104
23 0.365079365 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 118 g: Oscillospira; s: 176108 9
0.142857143 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 119 g:; s: 176115 45 0.714285714
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 120 g: Faecalibacterium; s: prausnitzii 176167 14
0.222222222 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 121 g: Ruminococcus; s: 176201
30 0.476190476 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 122 g: Coprococcus; s: 176300 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 123 g: Coprococcus; s: 176518 10
0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 124 g: Coprococcus; s: eutactus
176566 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 125 g: Oscillospira; s: 176705 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 126 g: Phascolarctobacterium; s:
176775 47 0.746031746 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 127 g: Phascolarctobacterium; s:
177058 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 128 g: Coprococcus; s: 177109 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 129 g: Oscillospira; s: 177111
39 0.619047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 130 g: Coprococcus; s: 177161 35
0.555555556 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 131 g: Clostridium; s: 177172 57
0.904761905 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 132 g: Coprococcus; s: 177217 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 133 g: Faecalibacterium; s:
prausnitzii 177228 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 134 177301
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 135 g: Coprococcus; s: 177403 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 136 g: Ruminococcus; s: 177463 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 137 g: Coprococcus; s: 177478 38
0.603174603 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 138 f: Coriobacteriaceae; g:; s: 177493 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 139 g: Coprococcus; s: 177518 12
0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 140 g: Coprococcus; s: 177586 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 141 g: Coprococcus; s: 177593 13
0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 142 g: Ruminococcus; s: 177600 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 143 g:; s: 177623 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 144 g: Ruminococcus; s: 177727 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 145 g: Ruminococcus; s: 177754
11 0.174603175 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 146 g: Coprococcus; s: 177775 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 147 g: Faecalibacterium; s:
prausnitzii 177800 20 0.317460317 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 148 g:
Ruminococcus; s: 177933 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 149 g:
Coprococcus; s: 177987 52 0.825396825 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 150 g:
Lachnospira; s: 178001 21 0.333333333 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 151 g:
Lachnospira; s: 178082 13 0.206349206 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 152 g:
Lachnospira; s: 178117 9 0.142857143 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 153 g:
Ruminococcus; s: 178146 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 154 g:
Coprococcus; s: 178151 10 0.158730159 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 155 g:
Ruminococcus; s: 178183 39 0.619047619 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 156
178205 18 0.285714286 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 157 g: Coprococcus; s: 178238 59
0.936507937 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 158 g: Coprococcus; s: 178370 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 159 g: Clostridium; s: 178385 13
0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 160 g: Faecalibacterium; s:
prausnitzii 178557 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 161 g:
Coprococcus; s: 178559 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 162 g:
Coprococcus; s: 178584 47 0.746031746 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 163 g:
Clostridium; s: 178629 45 0.714285714 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 164 g:
Coprococcus; s: 178738 25 0.396825397 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 165
178839 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 166 g:; s: 178852 31
0.492063492 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 167 g: Oscillospira; s: 178882 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 168 g: Coprococcus; s: 178961 18
0.285714286 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 169
g: Coprococcus; s: 178984 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 170 g:
Coprococcus; s: 179116 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 171 g:
Oscillospira; s: 179137 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 172 g:
Coprococcus; s: 179267 25 0.396825397 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 173 g:
Coprococcus; s: 179291 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 174 g:
Faecalibacterium; s: prausnitzii 179423 3 0.047619048 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
g:; s: 175 179536 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 176 179572
15 0.238095238 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 177 g: Ruminococcus; s: 179573 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 178 g: Ruminococcus; s: 179608 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 179 g:; s: 179644 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 180 g: Faecalibacterium; s:
prausnitzii 179647 29 0.46031746 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 181 g:
Ruminococcus; s: 179649 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 182 g:
Faecalibacterium; s: prausnitzii 179677 33 0.523809524 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
183 g: Coprococcus; s: 179834 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
184 g: Ruminococcus; s: 179911 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
185 g: Coprococcus; s: 179946 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
186 g: Coprococcus; s: 180107 8 0.126984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
187 g: Ruminococcus; s: 180130 15 0.238095238 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
188 g: Ruminococcus; s: 180133 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 189 f:
[Barnesiellaceae]; g:; s: 180136 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
190 g: Oscillospira; s: 180381 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
191 g: Ruminococcus; s: 180402 47 0.746031746 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
192 g:; s: 180468 11 0.174603175 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 193 g:
Oscillospira; s: 180509 34 0.53968254 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 194 g:
Ruminococcus; s: 180572 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 195 g:
Faecalibacterium; s: prausnitzii 180659 22 0.349206349 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
196 g: Oscillospira; s: 180665 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
197 g: Faecalibacterium; s: prausnitzii 180738 13 0.206349206 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 198 g: Ruminococcus; s: 180826 28 0.444444444 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 199 g: Ruminococcus; s: 180857 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 200 g: Ruminococcus; s: 180975 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 201 g: Oscillospira; s: 181016 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 202 g: Ruminococcus; s: 181025 40 0.634920635 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 203 g: Coprococcus; s: 181047 23 0.365079365 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 204 g: Coprococcus; s: 181056 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 205 g: Faecalibacterium; s: prausnitzii 181062 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 206 g: Oscillospira; s: 181139 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 207 g: Faecalibacterium; s:
prausnitzii 181160 31 0.492063492 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; 208 g:
Clostridium; s: 181176 25 0.396825397 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 209 g:
Coprococcus; s: 181269 14 0.222222222 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 210 g:
Coprococcus; s: 181422 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 211 g:
Faecalibacterium; s: prausnitzii 181466 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
g:; s: 212 181467 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 213 181560
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 214 g: Coprococcus; s: 181672 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 215 g: Coprococcus; s: 181853 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 216 g: Coprococcus; s: 181918 56
0.888888889 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 217 g: Coprococcus; s: 181969 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 218 g: Ruminococcus; s: 182054
58 0.920634921 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 219 g: Coprococcus; s: 182149 10
0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 220 g: Faecalibacterium; s:
prausnitzii 182456 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 221 g:
Lachnospira; s: 182538 15 0.238095238 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 222 g:
Coprococcus; s: 182588 8 0.126984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 223 g:
Ruminococcus; s: 182600 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 224 g:
Oscillospira; s: 182643 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 225
182799 56 0.888888889 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 226 g: Lachnospira; s: 182891 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 227 182986 10 0.158730159
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 228 g: Faecalibacterium; s: prausnitzii 183049 41
0.650793651 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 229 g: Faecalibacterium; s:
prausnitzii 183089 22 0.349206349 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 230 183104
6 0.095238095 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 231 f: Coriobacteriaceae; g:; s: 183157 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 232 g: Faecalibacterium; s:
prausnitzii 183162 7 0.111111111 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 233 g:
Oscillospira; s: 183245 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 234 g:
Ruminococcus; s: 183395 2 0.031746032 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 235 f:
[Barnesiellaceae]; g:; s: 183680 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
236 g: Coprococcus; s: 183748 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 237 g:; s: 183780 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
238 g: Faecalibacterium; s: prausnitzii 184000 47 0.746031746 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 239 g: Faecalibacterium; s: prausnitzii 184009 19
0.301587302 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 240 184013 8 0.126984127
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 241 g: Coprococcus; s: 184025 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 242 g: Coprococcus; s: 184511 10 0.158730159 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 243 g: Faecalibacterium; s: prausnitzii 184525 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 244 g: Coprococcus; s: 184678 39
0.619047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 245 g: Faecalibacterium; s:
prausnitzii 184725 4 0.063492063 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 246 g:; s: 184770
56 0.888888889 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 247 g: Coprococcus; s: 184821 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 248 g: Coprococcus; s: 184845 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 249 g: Ruminococcus; s: 184876 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 250 g: Lachnospira; s: 184897 47
0.746031746 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 251 g: Faecalibacterium; s:
prausnitzii 184905 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 252 g:
Coprococcus; s: 184940 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Christensenellaceae; 253 g:; s:
184996 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 254 g: Faecalibacterium; s:
prausnitzii 185042 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 255 g:
Oscillospira; s:
185159 4 0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 256 185175 3 0.047619048
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 257 g: Ruminococcus; s: 185222 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 258 185235 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
259 g: Coprococcus; s: 185324 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
260 g: Faecalibacterium; s: prausnitzii 185392 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 261 g: Ruminococcus; s: 185667 8 0.126984127 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 262 g: Coprococcus; s: 185715 18 0.285714286 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 263 g: Coprococcus; s: 185769 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 264 g: Faecalibacterium; s: prausnitzii 185821 12
0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 265 g: Coprococcus; s: eutactus
185861 23 0.365079365 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 266 g: Coprococcus; s: 186090 39
0.619047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 267 g: Ruminococcus; s: 186092
17 0.26984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 268 186133 15 0.238095238
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 269 g: Ruminococcus; s: 186289 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 270 g: Clostridium; s: 186319 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 271 g: Coprococcus; s: 186328 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 272 g: Faecalibacterium; s: prausnitzii 186350 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 273 g: Ruminococcus; s: 186389 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 274 g: Clostridium; s: 186392 29
0.46031746 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 275 g: Faecalibacterium; s:
prausnitzii 186554 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 276 g:
Ruminococcus; s: 186563 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 277 g:
Ruminococcus; s: callidus 186592 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
278 g: Coprococcus; s: 186614 60 0.952380952 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
279 g: Coprococcus; s: 186703 15 0.238095238 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 280 f:
Coriobacteriaceae; g: Collinsella; s: aerofaciens 186731 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 281 g: Coprococcus; s: 186780 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 282 g: Coprococcus; s: 186921 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 283 g: Coprococcus; s: 186969 15
0.238095238 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 284 g: Coprococcus; s: 186981 22
0.349206349 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 285 f: [Barnesiellaceae]; g:; s: 187056 38
0.603174603 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 286 g: Ruminococcus; s: 187181 9
0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 287 g: Ruminococcus; s: 187267
20 0.317460317 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 288 g: Oscillospira; s: 187321 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 289 g: Ruminococcus; s: 187356
60 0.952380952 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 290 g: Coprococcus; s: 187409 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 291 g: Oscillospira; s: 187466 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 292 187470 2 0.031746032
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 293 g: Coprococcus; s: 187490 49 0.777777778 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 294 f: Coriobacteriaceae; g: Collinsella; s:
187569 61 0.968253968 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 295 g: Coprococcus; s: 187668 50
0.793650794 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 296 g: Clostridium; s: 187709 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 297 g: Oscillospira; s: 187868
34 0.53968254 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 298 g: Coprococcus; s: 187956 26
0.412698413 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 299 188001 5 0.079365079
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 300 g: Ruminococcus; s: 188047 62 0.984126984 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 301 g: Coprococcus; s: 188079 36 0.571428571 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 302 g: Coprococcus; s: 188126 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 303 g: Faecalibacterium; s: prausnitzii 188276 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 304 g: Ruminococcus; s: 188316 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 305 g: Oscillospira; s: 188329 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 306 g: Faecalibacterium; s:
prausnitzii 188484 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 307 g:
Ruminococcus; s: 188625 19 0.301587302 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 308 g:
Coprococcus; s: 188789 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Christensenellaceae; 309 g:; s:
188881 9 0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 310 g:; s: 188918 30
0.476190476 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 311 g: Coprococcus; s: 188966 39
0.619047619 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 312 f: Coriobacteriaceae; g:; s: 188974 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 313 g: Coprococcus; s: 189011 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 314 g: Ruminococcus; s: 189035
22 0.349206349 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 315 g: Ruminococcus; s: 189064
46 0.73015873 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 316 g: Faecalibacterium; s:
prausnitzii 189092 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 317 g:
Faecalibacterium; s: prausnitzii 189110 14 0.222222222 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
318 g: Ruminococcus; s: 189116 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
319 g: Ruminococcus; s: 189147 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
320 g: Ruminococcus; s: 189150 31 0.492063492 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
321 g: Ruminococcus; s: 189152 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
322 g: Coprococcus; s: 189282 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
323 g: Faecalibacterium; s: prausnitzii 189294 43 0.682539683 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 324 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 189407 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: [Mogibacteriaceae]; 325 g:; s:
189459 12 0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 326 g: Coprococcus; s: 189478 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 327 g: Coprococcus; s: 189503 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 328 189626 1 0.015873016
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 329 g: Coprococcus; s: 189677 37 0.587301587 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 330 g: Coprococcus; s: 189708 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 331 g: Faecalibacterium; s: prausnitzii 189820 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 332 g: Ruminococcus; s: 189936 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 333 g:; s: 189937 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 334 g: Faecalibacterium; s:
prausnitzii 189960 6 0.095238095 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 335 f: [Barnesiellaceae]; g:; s:
189975 3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 336 g:; s: 189997 49
0.777777778 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 337 f: Coriobacteriaceae; g: Collinsella; s:
190299 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 338 g: Lachnospira; s: 190534 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 339 g: Coprococcus; s: 190599 13
0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 340 g: Coprococcus; s: 190679 12
0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 341
g: Coprococcus; s: eutactus 190766 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 342
g: Clostridium; s: 190844 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
343 g:; s: 190931 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 344 g:
Ruminococcus; s: 190975 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 345 f:
[Barnesiellaceae]; g:; s: 191238 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
346 g: Coprococcus; s: 191270 46 0.73015873 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
347 g: Oscillospira; s: 191389 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
348 g:; s: 191547 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 349 g:
Faecalibacterium; s: prausnitzii 191595 17 0.26984127 k: Bacteria;
p: Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 350 f:
Coriobacteriaceae; g: Collinsella; s: aerofaciens 191615 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 351 g: Ruminococcus; s: 191660 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 352 g: Faecalibacterium; s:
prausnitzii 191803 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 353 191874
8 0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 354 g: Ruminococcus; s: 192048 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 355 g: Faecalibacterium; s:
prausnitzii 192058 46 0.73015873 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 356 g:
Oscillospira; s: 192066 39 0.619047619 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 357 g:
Coprococcus; s: 192079 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 358 g:
Ruminococcus; s: 192218 12 0.19047619 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 359 g:
Coprococcus; s: 192231 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 360 g:
Faecalibacterium; s: prausnitzii 192263 19 0.301587302 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
361 g: Coprococcus; s: 192385 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 362 g:; s: 192515 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
363 g: Ruminococcus; s: bromii 192566 25 0.396825397 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
364 g: Faecalibacterium; s: prausnitzii 192654 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 365 g: Ruminococcus; s: 192893 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 366 g: Clostridium; s: 192958 19 0.301587302 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 367 g: Coprococcus; s: 193160 25 0.396825397 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 368 g: Coprococcus; s: eutactus 193191 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 369 g: Lachnospira; s: 193336 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 370 g: Ruminococcus; s: 193436 9
0.142857143 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 371 f: Coriobacteriaceae; g: Collinsella; s:
193551 13 0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 372 g: Coprococcus; s: 193575 39
0.619047619 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 373 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 193621 21 0.333333333 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 374 g:
Coprococcus; s: 193831 13 0.206349206 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 375 g:
Clostridium; s: 193969 14 0.222222222 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 376 g:
Coprococcus; s: 194001 10 0.158730159 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 377 g:
Coprococcus; s: 194008 59 0.936507937 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 378 g:
Coprococcus; s: 194104 45 0.714285714 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 379 g:
Coprococcus; s: 194110 24 0.380952381 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 380 g:
Lachnospira; s: 194123 8 0.126984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 381 g:
Coprococcus; s: 194223 55 0.873015873 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 382 g:
Ruminococcus; s: 194258 6 0.095238095 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 383 g:
Faecalibacterium; s: prausnitzii 194297 12 0.19047619 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
384 g: Ruminococcus; s: 194359 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
385 g: Coprococcus; s: 194360 10 0.158730159 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 386 f:
Alcaligenaceae; g: Sutterella; s: 194383 3 0.047619048 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
387 g: Faecalibacterium; s: prausnitzii 194417 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 388 g: Coprococcus; s: 194557 16 0.253968254 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 389 g: Coprococcus; s: 194646 2 0.031746032 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 390
f: [Odoribacteraceae]; g: Odoribacter; s: 194659 8 0.126984127 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 391 194692 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
392 g: Oscillospira; s: 194707 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
393 g: Lachnospira; s: 194727 33 0.523809524 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
394 g: Lachnospira; s: 194734 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
395 g: Coprococcus; s: 194816 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
396 g: Ruminococcus; s: 194868 25 0.396825397 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
397 g: Ruminococcus; s: 194933 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
398 g: Faecalibacterium; s: prausnitzii 194947 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 399 g: Ruminococcus; s: 195015 15 0.238095238 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 400 g: Lachnospira; s: 195532 43 0.682539683 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 401 g: Coprococcus; s: 195628 61 0.968253968 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 402 g: Coprococcus; s: 195716 5 0.079365079 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 403 g: Coprococcus; s: 195728 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 404 g: Coprococcus; s: 195752 28 0.444444444 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 405 g: Lachnospira; s: 195801 18 0.285714286 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 406 g: Faecalibacterium; s: prausnitzii 195855 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 407 g: Faecalibacterium; s:
prausnitzii 195876 14 0.222222222 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 408 g:
Coprococcus; s: 195929 18 0.285714286 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 409 g:
Coprococcus; s: 195933 11 0.174603175 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 410 g:
Oscillospira; s: 195947 7 0.111111111 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 411 g:
Ruminococcus; s: 196061 10 0.158730159 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 412 g:
Ruminococcus; s: 196112 5 0.079365079 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 413 g:
Ruminococcus; s: 196125 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 414 g:
Faecalibacterium; s: prausnitzii 196131 1 0.015873016 k: Bacteria;
p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 415 f:
[Odoribacteraceae]; g: Odoribacter; s: 196191 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 416 g: Oscillospira; s: 196246 50 0.793650794 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 417 g: Faecalibacterium; s: prausnitzii 196386 3
0.047619048 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 418 g:; s: 196462 13 0.206349206
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 419 g:; s: 196553 31 0.492063492 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
420 g: Oscillospira; s: 196951 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
421 g: Ruminococcus; s: 196991 8 0.126984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
422 g: Oscillospira; s: 197003 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
423 g: Coprococcus; s: 197022 23 0.365079365 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
424 g: Coprococcus; s: 197099 16 0.253968254 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
425 g: Oscillospira; s:
197107 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 426 g: Lachnospira; s: 197112 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 427 g: Coprococcus; s: 197341 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 428 g: Lachnospira; s: 197517 2
0.031746032 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 429 f: [Barnesiellaceae]; g:; s: 197581 29
0.46031746 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 430 g: Lachnospira; s: 197603 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 431 g: Coprococcus; s: 197649 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 432 g: Lachnospira; s: 197675 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 433 g: Coprococcus; s: 197708 33
0.523809524 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 434 g: Faecalibacterium; s:
prausnitzii 197757 34 0.53968254 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 435 g:
Faecalibacterium; s: prausnitzii 197807 8 0.126984127 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
436 g: Clostridium; s: 197890 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
437 g: Oscillospira; s: 197897 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
438 g: Coprococcus; s: 197943 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
439 g: Ruminococcus; s: 198034 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
440 g: Lachnospira; s: 198085 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
441 g: Faecalibacterium; s: prausnitzii 198194 23 0.365079365 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 442 g: Oscillospira; s: 198210 10 0.158730159 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 443 g: Ruminococcus; s: 198555 12 0.19047619 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 444 g: Coprococcus; s: 198909 26 0.412698413 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 445 g: Lachnospira; s: 198980 23 0.365079365 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 446 g: Ruminococcus; s: 199034 32 0.507936508 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 447 g: Clostridium; s: 199077 7 0.111111111 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 448 g: Coprococcus; s: 199081 12 0.19047619 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 449 g: Coprococcus; s: 199145 11 0.174603175 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 450 g: Faecalibacterium; s: prausnitzii 199228 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 451 g: Coprococcus; s: 199268 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 452 199300 20 0.317460317
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 453 g: Coprococcus; s: 199313 5 0.079365079 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 454 g: Coprococcus; s: 199337 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 455 g: Oscillospira; s: 199354 27 0.428571429 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 456
f: [Barnesiellaceae]; g:; s: 199388 20 0.317460317 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 457
g: Clostridium; s: 199421 33 0.523809524 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
458 g: Lachnospira; s: 199430 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
459 g: Faecalibacterium; s: prausnitzii 199491 11 0.174603175 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 460 g: Coprococcus; s: 199534 52 0.825396825 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 461 g:; s: 199543 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
462 g: Ruminococcus; s: 199568 18 0.285714286 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 463
g: Clostridium; s: 199686 7 0.111111111 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 464 f:
Coriobacteriaceae; g:; s: 199694 53 0.841269841 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 465
g: Clostridium; s: 199702 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 466 g:
Faecalibacterium; s: prausnitzii 202162 48 0.761904762 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
467 g: Ruminococcus; s: 204126 10 0.158730159 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
468 g: Oscillospira; s: 204352 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
469 g: Ruminococcus; s: 205613 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
470 g: Coprococcus; s: 206513 23 0.365079365 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
471 g: Oscillospira; s: 207252 17 0.26984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
472 g: Oscillospira; s: 207340 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
473 g:; s: 207487 33 0.523809524 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 474 g:
Lachnospira; s: 207994 19 0.301587302 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 475 g:
Ruminococcus; s: 208539 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae]; 476 g:; s:
208739 60 0.952380952 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 477 g: Faecalibacterium; s:
prausnitzii 208843 2 0.031746032 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 478 f: [Odoribacteraceae]; g:
Odoribacter; s: 208901 10 0.158730159 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 479 g:
Coprococcus; s: 209327 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 480 g:
Oscillospira; s: 209760 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 481 g:
Faecalibacterium; s: prausnitzii 210095 14 0.222222222 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
482 g: Ruminococcus; s: 210292 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
483 g: Oscillospira; s: 210542 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
484 g: Lachnospira; s: 210647 22 0.349206349 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
485 g: Ruminococcus; s: 212686 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
486 g: Oscillospira; s: 213394 16 0.253968254 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
487 g: Lachnospira; s: 213671 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
488 g:; s: 214031 14 0.222222222 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 489 g:; s: 214036
44 0.698412698 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 490 g:; s: 215097 9
0.142857143 k: Bacteria; p: Proteobacteria; c: Betaproteobacteria;
o: Burkholderiales; 491 f: Alcaligenaceae; g: Sutterella; s: 215963
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 492 g: Clostridium; s: 216010 21
0.333333333 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 493 g:; s: 216550 2
0.031746032 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 494 g:; s: 216599 27 0.428571429
k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 495 g:; s: 217109 8 0.126984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 496 g:; s: 221361 15 0.238095238 k: Bacteria;
p: Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales;
497 f: Enterobacteriaceae; g:; s: 221454 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
498 g: Ruminococcus; s: 223059 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
499 g: Ruminococcus; s: 227697 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
500 g: Ruminococcus; s: 227819 15 0.238095238 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 501 f:
Coriobacteriaceae; g:; s: 228199 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
502 g: Ruminococcus; s: 228748 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 503 g:; s: 229455 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
504 g: Ruminococcus; s: 229905 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
505 g:; s: 230578 6 0.095238095 k: Bacteria; p: Actinobacteria; c:
Coriobacteriia; o: Coriobacteriales; 506 f: Coriobacteriaceae; g:;
s: 231787 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 507 f:
Enterobacteriaceae; g:; s: 232417 11 0.174603175 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
508 g: Ruminococcus; s: 232900 7 0.111111111 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 509 f:
Coriobacteriaceae; g:; s:
232975 41 0.650793651 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 510 g: Oscillospira; s: 233052
10 0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 511 g:; s: 233648 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 512 g: Coprococcus; s: 234443 2
0.031746032 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 513 g:; s: 234447 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 514 g:; s: 234912 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
515 g: Clostridium; s: 235127 2 0.031746032 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 516 f:
Coriobacteriaceae; g:; s: 236811 2 0.031746032 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 517
f: Enterobacteriaceae; g: Enterobacter; s: 240271 8 0.126984127 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 518 g: Oscillospira; s: 243150 4 0.063492063 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 519 g:; s: 245625 35 0.555555556 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 520
g: Clostridium; s: 246330 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 521
f: Enterobacteriaceae; g:; s: 251456 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
522 g: Ruminococcus; s: flavefaciens 259212 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 523 259772 12 0.19047619 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
524 g: Coprococcus; s: 260559 11 0.174603175 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
525 g: Ruminococcus; s: 260842 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
526 g: Oscillospira; s: 261572 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
527 g:; s: 262024 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 528 g:
Oscillospira; s: 262060 11 0.174603175 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 529
262355 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 530 262668 19 0.301587302
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 531 g: Ruminococcus; s: 263074 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 532 g: Coprococcus; s: 263337 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 533 g: Oscillospira; s: 264325 2 0.031746032 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 534 g:; s: 265363 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 535 266726 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 536 g:
Coprococcus; s: 267042 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 537 g:
Ruminococcus; s: 267514 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 538 g:
Coprococcus; s: 268074 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 539 268733
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 540 269019 1 0.015873016
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 541 g: Oscillospira; s: 269145 32 0.507936508 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 542 g: Oscillospira; s: 269833 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 543 g: Ruminococcus; s: flavefaciens 270059 11
0.174603175 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 544 g: Oscillospira; s: 270162 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 545 g: Phascolarctobacterium; s:
270200 3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 546 270519 1 0.015873016
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 547 g: Oscillospira; s: 271430 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 548 g: Ruminococcus; s: 271563 11 0.174603175 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 549 g: Oscillospira; s: 274083 17 0.26984127 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 550 g: Oscillospira; s: 274569 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 551 g: Ruminococcus; s: 275097 3 0.047619048 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 552 f: Enterobacteriaceae; g:; s: 275237 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 553 g: Phascolarctobacterium; s:
275288 3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 554 g: Oscillospira; s: 275592 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 555 276650 2 0.031746032
k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 556 f: Coriobacteriaceae; g:; s: 278098 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 557 g: Ruminococcus; s: 278506 9
0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 558 g: Ruminococcus; s: 278609 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 559 g: Oscillospira; s: 278758 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 560 g: Oscillospira; s: 281015 8
0.126984127 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 561 f: Enterobacteriaceae; g:; s: 284014 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 562 f: Enterobacteriaceae; g:; s: 287514 38
0.603174603 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 563 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 287608 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 564 g:
Ruminococcus; s: 289110 5 0.079365079 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Veillonellaceae; 565 g:
Phascolarctobacterium; s: 289306 49 0.777777778 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
566 g: Oscillospira; s: 289709 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 567
f: Enterobacteriaceae; g:; s: 289752 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Veillonellaceae;
568 g: Phascolarctobacterium; s: 290253 3 0.047619048 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
569 g: Oscillospira; s: 290420 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
570 g: Ruminococcus; s: 290442 8 0.126984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
571 g: Ruminococcus; s: 291315 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Veillonellaceae;
572 g: Phascolarctobacterium; s: 291512 19 0.301587302 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
573 g: Coprococcus; s: 291644 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
574 g: Ruminococcus; s: 291902 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
575 g: Ruminococcus; s: 292091 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 576 292289 1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 577 f:
Enterobacteriaceae; g:; s: 292537 12 0.19047619 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
578 g: Faecalibacterium; s: prausnitzii 293508 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 579 g: Coprococcus; s: 293883 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Veillonellaceae; 580 g: Phascolarctobacterium; s: 294289 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 581 g: Ruminococcus; s: 294791 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 582 g: Coprococcus; s: 294909 1
0.015873016 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 583 f: [Barnesiellaceae]; g:; s: 294922 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 584 g: Faecalibacterium; s:
prausnitzii 295344 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 585 g:
Oscillospira; s: 295485 6 0.095238095 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 586 g:
Faecalibacterium; s: prausnitzii 295629 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
587 g: Coprococcus; s: 295974 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 588
g: Clostridium; s: perfringens 296420 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 589
g: Clostridium; s: 296837 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 590 g:
Clostridium; s: 296945 25 0.396825397 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 591 f:
Alcaligenaceae; g: Sutterella; s: 296960 5 0.079365079 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
592 g: Coprococcus; s: 297038 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
593 g: Ruminococcus; s: 297160 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
594 g: Ruminococcus; s: 297266 4 0.063492063 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
595 g:; s: 297385 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 596
g: Oscillospira; s: 298325 13 0.206349206 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
597 g: Ruminococcus; s: 298427 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Bacilli; o: Lactobacillales; f: Enterococcaceae; 598
g: Enterococcus; s: 299267 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 599
f: Enterobacteriaceae; g:; s: 299474 10 0.158730159 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 600 299820 31 0.492063492 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 601 g:
Oscillospira; s: 299837 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 602 g:
Faecalibacterium; s: prausnitzii 300297 14 0.222222222 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
603 g: Coprococcus; s: 300374 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
604 g: Oscillospira; s: 300378 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 605 300491 8 0.126984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 606 g:
Oscillospira; s: 300582 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 607
300829 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 608 g: Clostridium; s: 300851 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 609 g: Oscillospira; s: 300855
34 0.53968254 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 610 300952 25 0.396825397
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 611 g: Coprococcus; s: 301184 1 0.015873016 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 612 f: Enterobacteriaceae; g:; s: 301449 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 613 g: Clostridium; s: 301910 10
0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 614 g: Coprococcus; s: 302545 1
0.015873016 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 615 f: Coriobacteriaceae; g:; s: 302617 9
0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 616 g: Lachnospira; s: 302932 31
0.492063492 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 617 303379 1 0.015873016
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 618 303844 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
619 g: Coprococcus; s: 303864 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
620 g: Lachnospira; s: 304131 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
621 g: Oscillospira; s: 304427 19 0.301587302 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
622 g: Oscillospira; s: 304641 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 623
f: Enterobacteriaceae; g:; s: 304777 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
624 g: Oscillospira; s: 304779 9 0.142857143 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 625
g: Clostridium; s: perfringens 305016 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
626 g: Lachnospira; s: 305141 6 0.095238095 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 627 f:
Coriobacteriaceae; g:; s: 305288 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 628
g: Clostridium; s: 305608 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Veillonellaceae; 629 g:
Phascolarctobacterium; s: 306315 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
630 g: Oscillospira; s: 306413 8 0.126984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 631
g: Clostridium; s: 306704 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 632
307127 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 633 g: Lachnospira; s: 307238 18
0.285714286 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 634 g: Oscillospira; s: 308912 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 635 g:; s: 308957 1
0.015873016 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 636 g:; s: 309127 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 637 309433 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
638 g: Lachnospira; s: 309658 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 639
g: Clostridium; s: 309929 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 640 g:
Ruminococcus; s: 310301 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 641 g:
Faecalibacterium; s: prausnitzii 310945 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
642 g: Oscillospira; s: 312070 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
643 g:; s: 312515 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 644 g:
Oscillospira; s: 313387 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 645 g:
Coprococcus; s: 313672 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 646 g:
Lachnospira; s: 314053 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; 647 g:
Clostridium; s: 314582 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 648 g:
Oscillospira; s: 315200 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 649 g:
Ruminococcus; s: 315382 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 650 g:
Clostridium; s: 315391 20 0.317460317 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 651 g:
Faecalibacterium; s: prausnitzii 315831 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f:
[Mogibacteriaceae]; 652 g:; s: 315846 9 0.142857143 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 653 f:
[Barnesiellaceae]; g:; s: 316378 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 654 316732 27 0.428571429 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 655 g:
Lachnospira; s: 317948 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 656 g:
Ruminococcus; s: 318777 13 0.206349206 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Veillonellaceae; 657 g:
Phascolarctobacterium; s: 318865 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
658 g: Lachnospira; s: 318928 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
659 g: Ruminococcus; s: 319260 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
660 g:; s: 319275 51 0.80952381 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 661 g:
Faecalibacterium; s: prausnitzii 319455 20 0.317460317 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 662 g:; s: 320224 6 0.095238095 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
663 g: Ruminococcus; s: 320322 29 0.46031746 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
664 g: Lachnospira; s: 321096 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 665 321517 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 666 g:
Ruminococcus; s: 321774 16 0.253968254 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 667 g:
Coprococcus; s: 321907 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 668 g:
Coprococcus; s: 322223 2 0.031746032 k: Bacteria; p: Bacteroidetes;
c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 669 g:; s:
322258 6 0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 670 g: Oscillospira; s: 322367 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 671 322835 15 0.238095238
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 672 g: Lachnospira; s: 322962 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 673 g:; s: 323135 10 0.158730159 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
674 g: Ruminococcus; s: 323403 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
675 g: Oscillospira; s: 324214 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
676 g: Oscillospira; s: 324315 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 677
g: Clostridium; s: 324882 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae]; 678 g:; s:
325599 4 0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 679 g: Lachnospira; s: 326991 27
0.428571429 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 680 g: Clostridium; s: 327298 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 681 g: Clostridium; s: 327598 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 682 g:; s: 328059 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 683 328905 57 0.904761905
k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 684 g: Oscillospira; s: 328993 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 685 g: Coprococcus; s: 329096 2
0.031746032 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 686 f: Enterobacteriaceae; g:; s: 329688 10
0.158730159 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 687 f: Coriobacteriaceae; g: Collinsella; s:
stercoris 329798 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 688 330714
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 689 g: Clostridium; s: 331881 21
0.333333333 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 690 332027 7 0.111111111
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 691 g:; s: 332163 14 0.222222222 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
692 g: Lachnospira; s: 332450 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
693 g: Coprococcus; s: eutactus 333096 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
694 g: Ruminococcus; s: 333189 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
695 g: Oscillospira; s: 333380 4 0.063492063 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 696 f:
Alcaligenaceae; g: Sutterella; s: 333768 7 0.111111111 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
697 g: Oscillospira; s: 334215 4 0.063492063 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
698 g: Oscillospira; s: 334935 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
699 g: Oscillospira; s: 335910 22 0.349206349 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
700 g: Coprococcus; s: 336205 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
701 g: Coprococcus; s: 336338 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 702 337048 8 0.126984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 703 337511
14 0.222222222 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 704 338195 3 0.047619048
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 705 g:; s: 339087 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
706 g: Faecalibacterium; s: prausnitzii 339494 50 0.793650794 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 707 g: Faecalibacterium; s: prausnitzii 339712 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 708 340170 11 0.174603175
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 709 g: Ruminococcus; s: 340219 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 710 g: Faecalibacterium; s: prausnitzii 340794 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 711 g: Ruminococcus; s: 341004 4
0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 712 g: Oscillospira; s: 341489 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 713 g: Ruminococcus; s: 341885 9
0.142857143 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 714 341920 21 0.333333333
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 715 g: Faecalibacterium; s: prausnitzii 342268 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; 716 f: Peptostreptococcaceae; g: Clostridium; s:
metallolevans 342375 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 717 g:
Lachnospira; s: 342504 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 718 342666
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 719 343090 6 0.095238095
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 720 343104 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 721 344798 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 722 345362
2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 723 f:
Enterobacteriaceae; g:; s: 345540 10 0.158730159 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 724
f: Enterobacteriaceae; g:; s: 346302 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
725 g: Lachnospira; s: 346793 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Veillonellaceae;
726 g: Phascolarctobacterium; s: 347690 32 0.507936508 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
727 g: Oscillospira; s: 348009 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
728 g: Oscillospira; s: 349257 27 0.428571429 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
729 g: Lachnospira; s: 349431 18 0.285714286 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
730 g: Ruminococcus; s: 349798 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
731 g: Oscillospira; s: 349884 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
732 g: Ruminococcus; s: 350224 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
733 g: Ruminococcus; s: flavefaciens 350865 18 0.285714286 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 734 g: Lachnospira; s: 351357 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 735 352747 39 0.619047619 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
736 g: Coprococcus; s: 353632 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
737 g: Ruminococcus; s: 355298 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 738 355450 27 0.428571429 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 739 g:
Oscillospira; s: 355975 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 740 g:
Lachnospira; s: 356644 8 0.126984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 741 g:
Lachnospira; s: 356745 40 0.634920635 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 742 g:
Ruminococcus; s: 357046 59 0.936507937 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
743 g:; s: 357261 40 0.634920635 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 744 g:
Ruminococcus; s: 357449 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 745 g:
Coprococcus; s: 357529 21 0.333333333 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 746 g:
Clostridium; s: 357724 48 0.761904762 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 747 g:
Ruminococcus; s: bromii 357849 45 0.714285714 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 748 f:
Coriobacteriaceae; g: Collinsella; s: aerofaciens 358008 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 749 g: Faecalibacterium; s:
prausnitzii 358834 16 0.253968254 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 750 g:
Coprococcus; s: 359563 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 751 g:
Oscillospira; s: 359950 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 752 g:
Ruminococcus; s: 359993 12 0.19047619 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 753 g:
Coprococcus; s: eutactus 360147 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
754 g: Coprococcus; s: 361581 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
755 g: Faecalibacterium; s: prausnitzii 361702 55 0.873015873 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 756 g: Ruminococcus; s: 361966 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 757 g: Faecalibacterium; s: prausnitzii 362094 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 758 g: Faecalibacterium; s:
prausnitzii 362327 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 759 g:
Faecalibacterium; s: prausnitzii 362342 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
760 g: Ruminococcus; s: 362501 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
761 g: Coprococcus; s: eutactus 362765 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
762 g: Ruminococcus; s: 362793 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
763 g: Oscillospira; s: 362991 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
764 g: Ruminococcus; s: 363358 23 0.365079365 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
765 g: Faecalibacterium; s: prausnitzii 363389 16 0.253968254 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 766 g: Clostridium; s: 363442 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 767 g: Faecalibacterium; s: prausnitzii 363519 21
0.333333333 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 768 g:; s: 363646 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 769 g: Ruminococcus; s: 363794
22 0.349206349 k: Bacteria; p: Actinobacteria; c: Coriobacteriia;
o: Coriobacteriales; 770 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 364341 15 0.238095238 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 771 g:
Oscillospira; s: 364563 6 0.095238095 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 772
g: Faecalibacterium; s: prausnitzii 365118 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 773 g: Coprococcus; s: 365181 12 0.19047619 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 774 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 365628 24 0.380952381 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Veillonellaceae; 775 g:
Phascolarctobacterium; s: 365717 23 0.365079365 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
776 g: Faecalibacterium; s: prausnitzii 365842 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 777 g: Faecalibacterium; s: prausnitzii 365965 10
0.158730159 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 778 g: Ruminococcus; s: 366068 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 779 g: Faecalibacterium; s:
prausnitzii 366195 13 0.206349206 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 780 g:
Ruminococcus; s: bromii 366451 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 781
f: Enterobacteriaceae; g:; s: 366781 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 782
g: Clostridium; s: 367176 20 0.317460317 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
783 g: Oscillospira; s: 367232 39 0.619047619 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
784 g: Faecalibacterium; s: prausnitzii 367453 18 0.285714286 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 785 g: Coprococcus; s: 367688 56 0.888888889 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 786 g: Coprococcus; s: 367889 52 0.825396825 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 787 g: Coprococcus; s: 368127 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 788 g: Faecalibacterium; s: prausnitzii 368175 4
0.063492063 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 789 f: Coriobacteriaceae; g: Collinsella; s:
aerofaciens 368219 52 0.825396825 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 790 g:
Faecalibacterium; s: prausnitzii 368711 10 0.158730159 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 791 g:; s: 369354 1 0.015873016 k: Bacteria;
p: Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 792 f:
Coriobacteriaceae; g:; s: 369486 53 0.841269841 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
793 g: Lachnospira; s: 369555 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
794 g: Ruminococcus; s: 369602 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
795 g: Ruminococcus; s: bromii 369797 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
796 g: Ruminococcus; s: 369996 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
797 g: Faecalibacterium; s: prausnitzii 370075 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
[Mogibacteriaceae]; 798 g:; s: 370098 22 0.349206349 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
799 g: Lachnospira; s: 370287 20 0.317460317 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
800 g: Faecalibacterium; s: prausnitzii 372146 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 801 g: Oscillospira; s: 372348 3 0.047619048 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 802 g: Ruminococcus; s: 405780 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 803 g: Ruminococcus; s: 414949 4 0.063492063 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 804 f: Coriobacteriaceae; g: Collinsella; s:
415315 1 0.015873016 k: Bacteria; p: Actinobacteria; c:
Coriobacteriia; o: Coriobacteriales; 805 f: Coriobacteriaceae; g:
Collinsella; s: 422283 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 806 g:
Oscillospira; s: 437137 6 0.095238095 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 807 f:
Alcaligenaceae; g: Sutterella; s: 465433 1 0.015873016 k: Bacteria;
p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 808 g:; s: 470117 17 0.26984127 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
809 g: Clostridium; s: methylpentosum 508897 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 810 g: Coprococcus; s: 509516 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Bacilli; o: Lactobacillales; f:
Enterococcaceae; 811 g: Enterococcus; s: 512494 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Veillonellaceae; 812 g: Phascolarctobacterium; s: 514523 50
0.793650794 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 813 g: Faecalibacterium; s:
prausnitzii 515575 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 814 g:
Faecalibacterium; s: prausnitzii 518002 2 0.031746032 k: Bacteria;
p: Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales;
815 f: Enterobacteriaceae; g:; s: 518460 9 0.142857143 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
816 g: Coprococcus; s: 520413 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
817 g: Faecalibacterium; s: prausnitzii 521982 1 0.015873016 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 818 g:; s: 523140 16 0.253968254 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
819 g: Ruminococcus; s: 525215 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
820 g: Faecalibacterium; s: prausnitzii 525698 39 0.619047619 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 821 g: Faecalibacterium; s: prausnitzii 526665 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 822 g: Oscillospira; s: 528652 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 823 g: Faecalibacterium; s:
prausnitzii 529652 3 0.047619048 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 824 f: Alcaligenaceae; g:
Sutterella; s: 529789 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 825 g:
Ruminococcus; s: 533847 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 826 g:
Oscillospira; s: 534965 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 827
f: Enterobacteriaceae; g:; s: 535399 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
828 g: Oscillospira; s: 536584 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 829 g:; s: 539820 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
830 g: Oscillospira; s: 540402 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 831
f: Enterobacteriaceae; g:; s: 541119 2 0.031746032 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 832
f: Enterobacteriaceae; g:; s: 543824 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Bacilli; o: Lactobacillales; f: Enterococcaceae; 833
g: Enterococcus; s: 544996 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
834 g: Oscillospira; s: 548032 52 0.825396825 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
835 g: Oscillospira; s: 551822 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 836 553150 15 0.238095238 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 837 g:
Coprococcus; s: 555547 17 0.26984127 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Christensenellaceae; 838 g:; s:
556240 5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 839 g: Coprococcus; s: 556835 13
0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 840 g: Phascolarctobacterium; s:
559204 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 841 f:
Enterobacteriaceae; g:; s: 562244 4 0.063492063 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 842 f:
Alcaligenaceae; g: Sutterella; s: 562410 8 0.126984127 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 843 g:; s: 564334 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
844 g: Oscillospira; s: 566976 23 0.365079365 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 845
f: Enterobacteriaceae; g:; s: 571242 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
846 g: Ruminococcus; s: 574122 5 0.079365079 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
847 g: Oscillospira; s: 575041 6 0.095238095 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
848 g:; s: 578511 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 849 g:
Coprococcus; s: 579244 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 850 g:
Oscillospira; s: 581265 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 851 g:
Oscillospira; s: 584978 19 0.301587302 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 852 g:
Ruminococcus; s: 585227 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 853 g:
Oscillospira; s: 585989 4 0.063492063 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Veillonellaceae; 854 g:
Phascolarctobacterium; s: 586453 19 0.301587302 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 855 g:; s: 589076 4 0.063492063 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
856
g: Oscillospira; s: 591439 10 0.158730159 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
857 g:; s: 591540 7 0.111111111 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 858 g:
Coprococcus; s: 593686 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 859 g:
Coprococcus; s: 608244 5 0.079365079 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 860 g:
Ruminococcus; s: 622303 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; 861 g:
Clostridium; s: 644244 3 0.047619048 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Christensenellaceae; 862 g:; s:
663500 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 863 g: Phascolarctobacterium; s:
681779 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 864 f:
Enterobacteriaceae; g:; s: 686711 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 865 g:; s: 686972 1 0.015873016 k: Bacteria;
p: Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales;
866 f: Enterobacteriaceae; g:; s: 687940 1 0.015873016 k: Bacteria;
p: Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales;
867 f: Enterobacteriaceae; g: Enterobacter; s: arachidis 691423 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 868 f: Enterobacteriaceae; g:; s: 708285 20
0.317460317 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 869 731422 3 0.047619048
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Veillonellaceae; 870 g: Phascolarctobacterium; s: 740158 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 871 g: Phascolarctobacterium; s:
742358 1 0.015873016 k: Bacteria; p: Actinobacteria; c:
Coriobacteriia; o: Coriobacteriales; 872 f: Coriobacteriaceae; g:;
s: 743082 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Clostridiaceae; g:; s: 873 760594 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 874 g: Ruminococcus; s: 766768 1
0.015873016 k: Bacteria; p: Firmicutes; c: Bacilli; o:
Lactobacillales; f: Enterococcaceae; 875 g: Enterococcus; s: 772282
3 0.047619048 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 876 g:; s: 786708 3 0.047619048 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 877 f: Enterobacteriaceae; g:; s: 790466 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 878 g:; s: 797229 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 879 f: Enterobacteriaceae; g:; s: 798581 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 880 g: Ruminococcus; s: bromii
801210 1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 881 f: Alcaligenaceae; g:
Sutterella; s: 808609 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 882 g:
Ruminococcus; s: 811453 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 883 g:
Oscillospira; s: 816299 1 0.015873016 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 884 f:
Coriobacteriaceae; g:; s: 818516 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 885
g: Clostridium; s: botulinum 823634 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
886 g: Ruminococcus; s: 828776 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
887 g: Coprococcus; s: 832089 10 0.158730159 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
888 g:; s: 835346 1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 889 f:
Enterobacteriaceae; g: Erwinia; s: 835771 5 0.079365079 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 890 f: Enterobacteriaceae; g: Plesiomonas; s:
shigelloides 839964 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 891 g:
Oscillospira; s: 840279 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 892 f:
[Barnesiellaceae]; g:; s: 841635 20 0.317460317 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 893 f:
Alcaligenaceae; g: Sutterella; s: 842596 45 0.714285714 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 894 g: Coprococcus; s: 843553 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 895 g: Lachnospira; s: 846798 8 0.126984127 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 896
f: [Barnesiellaceae]; g:; s: 847427 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 897 f:
[Odoribacteraceae]; g: Odoribacter; s: 847670 15 0.238095238 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 898 847711 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 899 g:; s: 847728 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
900 g: Ruminococcus; s: 848669 11 0.174603175 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 901 f:
Alcaligenaceae; g: Sutterella; s: 848915 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
902 g: Oscillospira; s: 916143 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Veillonellaceae;
903 g: Phascolarctobacterium; s: 953855 18 0.285714286 k: Bacteria;
p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 904 g:; s: 1010876 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
905 g: Oscillospira; s: 1026524 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
906 g: Oscillospira; s: 1029949 18 0.285714286 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
907 g: Lachnospira; s: 1034960 2 0.031746032 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 908 f:
Coriobacteriaceae; g:; s: 1068836 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
909 g: Ruminococcus; s: 1105343 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; 910
g: Clostridium; s: 1105376 2 0.031746032 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 911 f:
Alcaligenaceae; g: Sutterella; s: 1106006 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 912 g: Ruminococcus; s: 1106362 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 913 g: Clostridium; s: 1108470 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 914 g: Ruminococcus; s: 1108656 2 0.031746032 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 915 f: Enterobacteriaceae; g:; s: 1108745 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 916 g:; s: 1112762 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 917 g: Oscillospira; s: 1123070
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 918 g: Ruminococcus; s: 1128398
2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 919 f:
Enterobacteriaceae; g:; s: 1129461 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Bacilli; o: Lactobacillales; f: Enterococcaceae; 920
g: Enterococcus; s: haemoperoxidus 1135616 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Bacilli; o: Lactobacillales; f:
Enterococcaceae; 921 g: Enterococcus; s: 1145098 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 922 g: Ruminococcus; s: gauvreauii 1503693 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 923 1584173 3 0.047619048
k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales;
924 f: [Barnesiellaceae]; g:; s: 1602307 17 0.26984127 k: Bacteria;
p: Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 925
f: Alcaligenaceae; g: Sutterella; s: 1624383 24 0.380952381 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 926 g: Lachnospira; s: 1646183 1 0.015873016 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 927 f: Coriobacteriaceae; g:; s: 1657484 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 928 g: Ruminococcus; s: 1663575
6 0.095238095 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 929 f:
Enterobacteriaceae; g:; s: 1719314 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
930 g: Faecalibacterium; s: prausnitzii 1726426 1 0.015873016 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 931 f: Enterobacteriaceae; g: Serratia; s:
1756274 1 0.015873016 k: Bacteria; p: Firmicutes; c: Bacilli; o:
Lactobacillales; f: Enterococcaceae; 932 g: Enterococcus; s:
1808742 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 933 g: Faecalibacterium; s:
prausnitzii 1811927 51 0.80952381 k: Bacteria; p: Actinobacteria;
c: Coriobacteriia; o: Coriobacteriales; 934 f: Coriobacteriaceae;
g: Collinsella; s: aerofaciens 1820513 9 0.142857143 k: Bacteria;
p: Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 935
f: Alcaligenaceae; g: Sutterella; s: 1855954 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 936 g: Clostridium; s: 1910658 24 0.380952381 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 937
f: [Barnesiellaceae]; g:; s: 1943669 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
938 g: Faecalibacterium; s: prausnitzii 1974536 2 0.031746032 k:
Bacteria; p: Proteobacteria; c: Betaproteobacteria; o:
Burkholderiales; 939 f: Alcaligenaceae; g: Sutterella; s: 2065341 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 940 g: Coprococcus; s: 2127939 2
0.031746032 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 941
f: Coriobacteriaceae; g:; s: 2196877 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
942 g: Oscillospira; s: 2201995 28 0.444444444 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 943 f:
Alcaligenaceae; g: Sutterella; s: 2203165 4 0.063492063 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 944 g: Oscillospira; s: 2250345 9 0.142857143 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 945 g: Clostridium; s: hathewayi 2256425 12
0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 946 g:; s: 2307779 47
0.746031746 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 947 g: Oscillospira; s: 2313540
23 0.365079365 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 948 g: Lachnospira; s: 2318202 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 949 g: Oscillospira; s: 2365690
38 0.603174603 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 950 g: Faecalibacterium; s:
prausnitzii 2423305 7 0.111111111 k: Bacteria; p: Actinobacteria;
c: Coriobacteriia; o: Coriobacteriales; 951 f: Coriobacteriaceae;
g:; s: 2442706 40 0.634920635 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Christensenellaceae; 952 g:; s:
2496050 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 953 g: Ruminococcus; s: 2532909
4 0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 954 2544615 63 1 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 955 g: Faecalibacterium; s: prausnitzii 2582263 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 956 f: Enterobacteriaceae; g:; s: 2617854 38
0.603174603 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; f: Rikenellaceae; 957 g:; s: 2642538 5 0.079365079
k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales;
958 f: [Odoribacteraceae]; g: Odoribacter; s: 2710761 1 0.015873016
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Veillonellaceae; 959 g: Phascolarctobacterium; s: 2740950 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 960 g: Coprococcus; s: 2749126 2
0.031746032 k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria;
o: Enterobacteriales; 961 f: Enterobacteriaceae; g:; s: 2781880 8
0.126984127 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 962 g: Oscillospira; s: 2801994
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 963 g: Phascolarctobacterium; s:
2840201 35 0.555555556 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Clostridiaceae; 964 g: Clostridium; s: 2943548
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 965 g: Ruminococcus; s: 2949920
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 966 2963287 3 0.047619048
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 967 g:; s: 2978122 8 0.126984127 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
968 g: Oscillospira; s: 2979308 43 0.682539683 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
969 g: Ruminococcus; s: 2985051 2 0.031746032 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 970 f:
Coriobacteriaceae; g:; s: 3015509 14 0.222222222 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
971 g: Ruminococcus; s: 3016478 6 0.095238095 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
972 g: Ruminococcus; s: 3023610 21 0.333333333 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
973 g: Lachnospira; s: 3028318 7 0.111111111 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
974 g:; s: 3090117 2 0.031746032 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 975 f: [Barnesiellaceae]; g:; s:
3123133 4 0.063492063 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 976 f: Alcaligenaceae; g:
Sutterella; s: 3138798 24 0.380952381 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Veillonellaceae; 977 g:
Phascolarctobacterium; s: 3141342 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
978 g: Coprococcus; s: 3160267 8 0.126984127 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 979 f:
[Barnesiellaceae]; g:; s: 3190479 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 980 g:; s: 3235048 7 0.111111111 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
981 g: Ruminococcus; s: 3257594 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
982 g: Oscillospira; s: 3302039 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
983 g: Oscillospira; s: 3325984 34 0.53968254 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
984 g: Coprococcus; s: 3369303 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
985 g:; s: 3424188 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 986 g:
Lachnospira; s: 3430935 6 0.095238095 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 987 g:
Faecalibacterium; s: prausnitzii 3443092 13 0.206349206 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 988 g: Faecalibacterium; s: prausnitzii 3505877 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 989 g: Faecalibacterium; s:
prausnitzii 3507351 6 0.095238095 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Veillonellaceae; 990 g:
Phascolarctobacterium; s: 3522002 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: [Mogibacteriaceae];
991 g:; s: 3568684 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 992 g:
Oscillospira; s: 3589845 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Ruminococcaceae; 993 g:
Ruminococcus; s: 3613745 7 0.111111111 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 994 g:
Lachnospira; s: 3648884 2 0.031746032 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Lachnospiraceae; 995 g:
Coprococcus; s: 3734841 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 996
3805726 4 0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 997 g:; s: 3903651 54
0.857142857 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 998 g: Oscillospira; s: 3931537
41 0.650793651 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 999 g: Clostridium; s: 3991008 3
0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1000 g: Faecalibacterium; s:
prausnitzii 4035247 23 0.365079365 k: Bacteria; p: Bacteroidetes;
c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1001 g:; s:
4039230 25 0.396825397 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Lachnospiraceae; 1002 g: Lachnospira; s:
4060645 7 0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1003 g: Lachnospira; s: 4093791
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 1004 g:; s: 4095596 56
0.888888889 k: Bacteria; p: Proteobacteria; c: Betaproteobacteria;
o: Burkholderiales; 1005 f: Alcaligenaceae; g: Sutterella; s:
4111715 7 0.111111111 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 1006 f:
Enterobacteriaceae; g:; s: 4120404 7 0.111111111 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 1007 f:
Alcaligenaceae; g: Sutterella; s: 4142052 1 0.015873016 k:
Bacteria; p: Proteobacteria; c: Betaproteobacteria; o:
Burkholderiales; 1008 f: Alcaligenaceae; g: Sutterella; s: 4194837
13 0.206349206 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1009 g: Coprococcus; s: 4217226
1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 1010 f: Alcaligenaceae; g:
Sutterella; s: 4238179 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 1011
4282363 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1012 g: Faecalibacterium; s:
prausnitzii 4289858 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 1013
4290144 1 0.015873016 k: Bacteria; p: Firmicutes; c: Bacilli; o:
Lactobacillales; f: Enterococcaceae; 1014 g: Enterococcus; s:
4296216 26 0.412698413 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Ruminococcaceae; 1015 g: Ruminococcus; s:
4296764 3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 1016 g:; s: 4296772 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1017 g: Coprococcus; s: 4303851
2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1018 g: Ruminococcus; s: 4303855
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1019 g: Ruminococcus; s: 4304843
6 0.095238095 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 1020 f: Coriobacteriaceae; g:; s: 4305261 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 1021 g:; s: 4308811 1
0.015873016 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 1022 f: Coriobacteriaceae; g:; s: 4311621 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 1023 g: Phascolarctobacterium;
s: 4315688 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Clostridiaceae; 1024 g: Clostridium; s:
celatum 4317896 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 1025 g:
Oscillospira; s: 4321292 2 0.031746032 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1026
f: Enterobacteriaceae; g: Proteus; s:
4325533 15 0.238095238 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1027 g:; s:
4325836 2 0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 1028 4326080 32
0.507936508 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; 1029 g: Clostridium; s: 4326869
19 0.301587302 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1030 g: Ruminococcus; s: 4328189
3 0.047619048 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 1031 f:
Enterobacteriaceae; g: Serratia; s: 4331723 32 0.507936508 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 1032 g: Ruminococcus; s: 4331760 16 0.253968254 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f:
Rikenellaceae; 1033 g: Alistipes; s: indistinctus 4332078 11
0.174603175 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 1034 4333020 1 0.015873016
k: Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 1035 f: Enterobacteriaceae; g:; s: 4335402 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1036 g: Coprococcus; s: 4336423
3 0.047619048 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1037 g: Faecalibacterium; s:
prausnitzii 4336943 8 0.126984127 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1038 g:; s:
4337970 3 0.047619048 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 1039 f: [Barnesiellaceae]; g:; s:
4338624 7 0.111111111 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 1040 f: Alcaligenaceae; g:
Sutterella; s: 4339145 1 0.015873016 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 1041 f:
Coriobacteriaceae; g:; s: 4341497 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 1042 f:
Alcaligenaceae; g: Sutterella; s: 4349517 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 1043 4353658 2 0.031746032 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Veillonellaceae;
1044 g: Phascolarctobacterium; s: 4354477 33 0.523809524 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 1045 f: Enterobacteriaceae; g:; s: 4356080 13
0.206349206 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 1046 f: [Barnesiellaceae]; g:; s: 4357223 2
0.031746032 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1047 g: Ruminococcus; s: 4359216
5 0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1048 g: Faecalibacterium; s:
prausnitzii 4361768 1 0.015873016 k: Bacteria; p: Actinobacteria;
c: Coriobacteriia; o: Coriobacteriales; 1049 f: Coriobacteriaceae;
g:; s: 4362724 21 0.333333333 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 1050 g:
Oscillospira; s: 4364469 2 0.031746032 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1051
f: Enterobacteriaceae; g: Brenneria; s: alni 4364747 38 0.603174603
k: Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; g:; s: 1052 4366089 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1053 g: Oscillospira; s: 4366834 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 1054 f:
Alcaligenaceae; g: Sutterella; s: 4370657 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 1055 g: Clostridium; s: perfringens 4371341 6
0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 1056 g: Phascolarctobacterium;
s: 4371724 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Ruminococcaceae; 1057 g: Ruminococcus; s:
4371786 2 0.031746032 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 1058 f: [Barnesiellaceae]; g:; s:
4375000 2 0.031746032 k: Bacteria; p: Proteobacteria; c:
Gammaproteobacteria; o: Enterobacteriales; 1059 f:
Enterobacteriaceae; g:; s: 4379449 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Erysipelotrichi; o: Erysipelotrichales; 1060 f:
Erysipelotrichaceae; g: Clostridium; s: saccharogumia 4381430 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1061 g: Faecalibacterium; s:
prausnitzii 4381639 4 0.063492063 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 1062 g:
Ruminococcus; s: 4385756 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 1063
4387208 1 0.015873016 k: Bacteria; p: Firmicutes; c: Bacilli; o:
Lactobacillales; f: Enterococcaceae; 1064 g: Enterococcus; s:
4387344 6 0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1065 g: Faecalibacterium; s:
prausnitzii 4391009 2 0.031746032 k: Bacteria; p: Proteobacteria;
c: Betaproteobacteria; o: Burkholderiales; 1066 f: Alcaligenaceae;
g: Sutterella; s: 4391738 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Bacilli; o: Lactobacillales; f: Enterococcaceae; 1067 g:
Enterococcus; s: 4393396 8 0.126984127 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 1068 f:
[Barnesiellaceae]; g:; s: 4397092 2 0.031746032 k: Bacteria; p:
Actinobacteria; c: Coriobacteriia; o: Coriobacteriales; 1069 f:
Coriobacteriaceae; g:; s: 4400482 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
1070 g: Clostridium; s: butyricum 4401045 2 0.031746032 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Clostridiaceae; 1071 g: Clostridium; s: 4402537 11 0.174603175 k:
Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 1072 f: Coriobacteriaceae; g:; s: 4402605 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 1073 g:; s: 4403113 33
0.523809524 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1074 g: Faecalibacterium; s:
prausnitzii 4403259 6 0.095238095 k: Bacteria; p: Actinobacteria;
c: Coriobacteriia; o: Coriobacteriales; 1075 f: Coriobacteriaceae;
g:; s: 4403632 53 0.841269841 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 1076 g:
Coprococcus; s: 4407939 5 0.079365079 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1077
f: Enterobacteriaceae; g:; s: 4410097 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f:
Christensenellaceae; 1078 g:; s: 4414821 1 0.015873016 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1079 g: Ruminococcus; s: 4416113 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1080
f: Enterobacteriaceae; g:; s: 4416646 29 0.46031746 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1081 g: Ruminococcus; s: 4416951 7 0.111111111 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1082 g: Ruminococcus; s: 4419621 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Betaproteobacteria; o: Burkholderiales; 1083 f:
Alcaligenaceae; g: Sutterella; s: 4419650 47 0.746031746 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 1084 g: Coprococcus; s: 4421273 17 0.26984127 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Ruminococcaceae; 1085 g: Oscillospira; s: 4424598 6 0.095238095 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
Lachnospiraceae; 1086 g: Lachnospira; s: 4425571 12 0.19047619 k:
Bacteria; p: Proteobacteria; c: Gammaproteobacteria; o:
Enterobacteriales; 1087 f: Enterobacteriaceae; g:; s: 4425669 5
0.079365079 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1088 g: Coprococcus; s: 4426249
1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1089 g: Oscillospira; s: 4427459
12 0.19047619 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1090 g: Ruminococcus; s: 4428676
4 0.063492063 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Lachnospiraceae; 1091 g: Coprococcus; s: 4429986
1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 1092 f: Alcaligenaceae; g:
Sutterella; s: 4433274 1 0.015873016 k: Bacteria; p:
Proteobacteria; c: Gammaproteobacteria; o: Enterobacteriales; 1093
f: Enterobacteriaceae; g:; s: 4434334 57 0.904761905 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
g:; s: 1094 4437359 2 0.031746032 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 1095 g:
Oscillospira; s: 4439530 3 0.047619048 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 1096
4440335 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Christensenellaceae; 1097 g:; s: 4441081 2
0.031746032 k: Bacteria; p: Actinobacteria; c: Coriobacteriia; o:
Coriobacteriales; 1098 f: Coriobacteriaceae; g:; s: 4443143 7
0.111111111 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Ruminococcaceae; 1099 g: Ruminococcus; s: 4444277
2 0.031746032 k: Bacteria; p: Bacteroidetes; c: Bacteroidia; o:
Bacteroidales; 1100 f: [Odoribacteraceae]; g: Odoribacter; s:
4444529 1 0.015873016 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1101 g:; s:
4444790 6 0.095238095 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Veillonellaceae; 1102 g: Phascolarctobacterium;
s: 4445226 1 0.015873016 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 1103 f: [Barnesiellaceae]; g:; s:
4446320 25 0.396825397 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Clostridiaceae; g:; s: 1104 4449236 1
0.015873016 k: Bacteria; p: Proteobacteria; c: Betaproteobacteria;
o: Burkholderiales; 1105 f: Alcaligenaceae; g: Sutterella; s:
4451901 1 0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: [Mogibacteriaceae]; 1106 g:; s: 4452633 1
0.015873016 k: Bacteria; p: Firmicutes; c: Clostridia; o:
Clostridiales; f: Clostridiaceae; g:; s: 1107 4453060 3 0.047619048
k: Bacteria; p: Firmicutes; c: Bacilli; o: Lactobacillales; f:
Enterococcaceae; 1108 g: Enterococcus; s: 4454586 53 0.841269841 k:
Bacteria; p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 1109
f: [Odoribacteraceae]; g: Odoribacter; s: 4455005 1 0.015873016 k:
Bacteria; p: Firmicutes; c: Clostridia; o: Clostridiales; f:
[Mogibacteriaceae]; 1110 g:; s: 4456702 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1111 g: Ruminococcus; s: 4457064 1 0.015873016 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; f: Rikenellaceae;
1112 g:; s: 4457427 44 0.698412698 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Lachnospiraceae; 1113
g: Lachnospira; s: 4459196 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
1114 g: Lachnospira; s: 4460847 32 0.507936508 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1115 g: Ruminococcus; s: 4463709 45 0.714285714 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
1116 g: Coprococcus; s: 4466707 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
1117 g: Coprococcus; s: 4468461 1 0.015873016 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:;
s: 1118 4470582 1 0.015873016 k: Bacteria; p: Firmicutes; c:
Clostridia; o: Clostridiales; f: Ruminococcaceae; 1119 g:
Faecalibacterium; s: prausnitzii 4470870 2 0.031746032 k: Bacteria;
p: Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 1120 f:
[Barnesiellaceae]; g:; s: 4471854 3 0.047619048 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Lachnospiraceae;
1121 g: Coprococcus; s: 4472091 45 0.714285714 k: Bacteria; p:
Firmicutes; c: Clostridia; o: Clostridiales; f: Ruminococcaceae;
1122 g: Ruminococcus; s: 4472721 47 0.746031746 k: Bacteria; p:
Bacteroidetes; c: Bacteroidia; o: Bacteroidales; 1123 f:
[Odoribacteraceae]; g: Odoribacter; s: 4473506 5 0.079365079 k:
Bacteria; p: Proteobacteria; c: Betaproteobacteria; o:
Burkholderiales; 1124 f: Alcaligenaceae; g: Sutterella; s: 4474255
1 0.015873016 k: Bacteria; p: Proteobacteria; c:
Betaproteobacteria; o: Burkholderiales; 1125 f: Alcaligenaceae; g:
Sutterella; s: 4476561 12 0.19047619 k: Bacteria; p: Bacteroidetes;
c: Bacteroidia; o: Bacteroidales; 1126 f: [Barnesiellaceae]; g:; s:
4476780 20 0.317460317 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1127 g:; s:
4476877 4 0.063492063 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; 1128 f: [Odoribacteraceae]; g:
Odoribacter; s: 4478840 1 0.015873016 k: Bacteria; p: Firmicutes;
c: Clostridia; o: Clostridiales; f: Clostridiaceae; g:; s: 1129
4481131 62 0.984126984 k: Bacteria; p: Firmicutes; c: Clostridia;
o: Clostridiales; f: Ruminococcaceae; 1130 g: Faecalibacterium; s:
prausnitzii 4481613 2 0.031746032 k: Bacteria; p: Actinobacteria;
c: Coriobacteriia; o: Coriobacteriales; 1131 f: Coriobacteriaceae;
g: Collinsella; s: aerofaciens 4481624 2 0.031746032 k: Bacteria;
p: Firmicutes; c: Clostridia; o: Clostridiales; f: Clostridiaceae;
g:; s: 1132 4483570 1 0.015873016 k: Bacteria; p: Bacteroidetes; c:
Bacteroidia; o: Bacteroidales; f: Rikenellaceae; 1133 g:; s:
.sup.1Operational taxonomic units (OTUs) which cluster bacteria
based on 16S rRNA sequence identity. .sup.2In this column, letters
refer to phylogenetic classifications (e.g., "k:" refers to
"kingdom," "p:" refers to phylum, and so on).
[0113] Table 6 lists exemplary bacterial genera and the number of
OTUs identified in GreenGenes database (and recited in Table 5).
[0114] Columns: [0115] A--Taxonomy for that genus [0116] B--Number
of OTUs that are found in healthy stool donors that belong to this
genus [0117] C--SEQ ID NOs associated with OTUs
TABLE-US-00006 [0117] TABLE 6 Exemplary Genera Useful in the
Present Invention A.sup.3 B C k_Bacteria; p_Proteobacteria;
c_Gammaproteobacteria; o_Enterobacteriales; 8 1134 to 1141
f_Enterobacteriaceae; g_Proteus k_Bacteria; p_Bacteroidetes;
c_Bacteroidia; o_Bacteroidales; f_Rikenellaceae; g.sub.-- 34 1142
to 1175 k_Bacteria; p_Firmicutes; c_Clostridia; o_Clostridiales;
f_Ruminococcaceae; 1 1176 g_Clostridium k_Bacteria; p_Firmicutes;
c_Clostridia; o_Clostridiales; f_Lachnospiraceae; 2 1177 to 1178
g_Clostridium k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 291 1179 to 1469 f_Enterobacteriaceae;
g.sub.-- k_Bacteria; p_Firmicutes; c_Clostridia; o_Clostridiales;
f_Lachnospiraceae; 248 1470 to 1717 g_Coprococcus k_Bacteria;
p_Firmicutes; c_Clostridia; o_Clostridiales; f_Veillonellaceae; 28
1718 to 1745 g_Phascolarctobacterium k_Bacteria; p_Firmicutes;
c_Clostridia; o_Clostridiales; f_Lachnospiraceae; 1 1746
g_Ruminococcus k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 11 1747 to 1757 f_Enterobacteriaceae;
g_Serratia k_Bacteria; p_Bacteroidetes; c_Bacteroidia;
o_Bacteroidales; f_Odoribacteraceae; 14 1758 to 1771 g_Odoribacter
k_Bacteria; p_Firmicutes; c_Clostridia; o_Clostridiales;
f_Clostridiaceae; g.sub.-- 322 1772 to 2093 k_Bacteria;
p_Firmicutes; c_Clostridia; o_Clostridiales; f_Clostridiaceae; 113
2094 to 2206 g_Clostridium k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Mogibacteriaceae; g.sub.-- 47 2207 to 2253
k_Bacteria; p_Bacteroidetes; c_Bacteroidia; o_Bacteroidales;
f_Rikenellaceae; 2 2254 to 2255 g_Alistipes k_Bacteria;
p_Firmicutes; c_Clostridia; o_Clostridiales; f_Ruminococcaceae; 188
2256 to 2443 g_Oscillospira k_Bacteria; p_Firmicutes;
c_Erysipelotrichi; o_Erysipelotrichales; 2 2444 to 2445
f_Erysipelotrichaceae; g_Clostridium k_Bacteria; p_Proteobacteria;
c_Gammaproteobacteria; o_Enterobacteriales; 6 2446 to 2451
f_Enterobacteriaceae; g_Plesiomonas k_Bacteria; p_Firmicutes;
c_Bacilli; o_Lactobacillales; f_Enterococcaceae; 41 2452 to 2492
g_Enterococcus k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Lachnospiraceae; 63 2493 to 2555 g_Lachnospira
k_Bacteria; p_Actinobacteria; c_Coriobacteriia; o_Coriobacteriales;
83 2556 to 2638 f_Coriobacteriaceae; g.sub.-- k_Bacteria;
p_Bacteroidetes; c_Bacteroidia; o_Bacteroidales; f_Barnesiellaceae;
g.sub.-- 31 2639 to 2669 k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Ruminococcaceae; 214 2670 to 2883 g_Ruminococcus
k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 28 2884 to 2911 f_Enterobacteriaceae;
g_Erwinia k_Bacteria; p_Proteobacteria; c_Betaproteobacteria;
o_Burkholderiales; 37 2912 to 2948 f_Alcaligenaceae; g_Sutterella
k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 10 2950 to 2958 f_Enterobacteriaceae;
g_Enterobacter k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 12 2959 to 2970 f_Enterobacteriaceae;
g_Citrobacter k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Christensenellaceae; g.sub.-- 52 2971 to 3022
k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 1 3023 f_Enterobacteriaceae; g_Xenorhabdus
k_Bacteria; p_Proteobacteria; c_Gammaproteobacteria;
o_Enterobacteriales; 2 3024 to 3025 f_Enterobacteriaceae;
g_Brenneria k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Peptostreptococcaceae; 3 3026 to 3028
g_Clostridium k_Bacteria; p_Firmicutes; c_Clostridia;
o_Clostridiales; f_Ruminococcaceae; 131 3029 to 3159
g_Faecalibacterium k_Bacteria; p_Actinobacteria; c_Coriobacteriia;
o_Coriobacteriales; 26 3160 to 3185 f_Coriobacteriaceae;
g_Collinsella .sup.3In this column, letters refer to phylogenetic
classifications (e.g., "k" refers to "kingdom," "p" refers to
phylum, and so on).
[0118] In an embodiment, a bacterial strain is included in the
pharmaceutical composition of the invention based on its abundance
in donors whose stool was used for successful or unsuccessful fecal
microbiota transplants (FMTs) in a patient suffering from a gut
dysbiosis disorder, e.g., caused by a previous or current
anti-cancer therapy.
[0119] In an embodiment, a bacterial strain is included in the
pharmaceutical composition of the invention based on its presence
in the stool samples of donors whose stool was used for FMTs which
provided a therapeutically effective result in a GI disorder
patient.
[0120] In an embodiment, a bacterial strain is included in the
pharmaceutical composition of the invention based on its ability to
engraft in a recipient. For example, the recipient may be a FMT
recipient who received stool transplant from a donor. The bacterial
strain is considered to successfully engraft if the strain is
abundant in donors and also increased in recipient patients. In
some embodiments, the selected bacterial strain exhibits enhanced
ability to colonize the mucosa, i.e., is a good mucosal
colonizer.
[0121] In various embodiments, a bacterial strain may be selected
for inclusion in the bacterial mixture based on its ability to
directly inhibit a bacterium (e.g., pathogenic bacterium) through
production of a secreted product. In some embodiments, a bacterial
strain may be selected for inclusion in the bacterial mixture based
on its ability to directly compete with the pathogenic bacteria for
a niche and/or for nutrients. In embodiments, a bacterial strain
may be selected for inclusion in the bacterial mixture based on its
ability to decolonize a pathogenic bacterium. In embodiments, a
bacterial strain may be selected for inclusion in the bacterial
mixture based on its ability to eradicate a pathogenic
bacterium.
[0122] In an embodiment, a bacterial strain may be selected for
inclusion in a bacterial mixture based on its ability to enhance
production of SCFAs, which increases the thickness of the mucus
layer, maintains the health of colonocytes, increases butyrate
levels in the gut, inhibits nitric oxide synthase activity, reduces
the concentration of host-derived nitrate levels in the gut, and/or
induces IgA production. As used herein, SCFAs refer to fatty acids
with an aliphatic tail of less than six carbon atoms. Illustrative
SCFAs include, but are not limited to, formic acid, acetic acid,
propionic acid, butyric acid, isobutyric acid, valeric acid, and
isovaleric acid. Without wishing to be bound by theory, SCFAs are
involved in mediation of GI inflammation, and SOFA-producing
bacteria are associated with sustained clinical remission in UC.
Accordingly, in some embodiments, a bacterial strain is selected
based on its ability to produce increased levels of SCFAs.
Additionally, in some embodiments, a bacterial strain is selected
for its ability to complement the capacity of a functionally
deficient microbial community (e.g., the microbial community of a
patient infected and/or colonized by a pathogenic bacteria) to
produce levels of SCFAs comparable to healthy individuals.
[0123] In an embodiment, a bacterial strain may be selected for
inclusion in a bacterial mixture based on its ability to promote
restoration of mucosal barrier functions. For example, in some
embodiments, a bacterial strain may be selected based on its
ability to enable mucosal healing, improve mucosal barrier
function, and/or to reduce inflammation. Without wishing to be
bound by theory, it is believed that inclusion of such bacterial
strains reinforces both the structural and chemical barrier
functions of the mucosa by displacing pathogenic mucus degrading
microorganisms and support mucosal repair. In an embodiment, the
inclusion of such bacterial strain impacts numerous inflammatory
pathways linked to inappropriate microbial exposure.
[0124] Accordingly, in some embodiments, the pharmaceutical
composition of the invention includes a bacterial strain that
prevents and/or reduces the loss of mucus thickness associated with
various GI disorders. In some embodiments, the pharmaceutical
composition of the invention includes a bacterial strain that
results in a reduction of bacterial penetration or bacterial load
in the mucus. In some embodiments, the pharmaceutical composition
of the invention includes a bacterial strain that reduces
sulfate-reducing bacteria (SRB) in a subject.
[0125] Additional criteria that may be utilized for selecting a
bacterial strain for inclusion in the pharmaceutical composition of
the invention include, but are not limited to, the ability of the
bacterial strain to inhibit IgA-degrading bacteria, the ability of
the bacterial strain to inhibit serotonin-producing and
serotonin-inducing bacteria, the ability of the bacterial strain to
enhance tryptophan availability, the ability of the bacterial
strain to produce anti-inflammatory zwitterionic polysaccharides,
modification of signaling molecules interacting with the Aryl
Hydrocarbon Receptor, and/or the ability of the bacterial strain to
block the vitamin D receptor (VCD) or vitamin D signaling.
[0126] In various embodiments, individual bacterial strains are
initially selected from Table 5 or Table 6 and subsequently pooled
to form a mixture of bacterial strains. For example, in an
embodiment, a mixture of bacterial strains may be formed by
including one or more strains that has a 16S rRNA sequence that is
at least about 97% identical with the 16S rRNA sequence of any one
of the operational taxonomic units provided in Table 5 or Table 6,
one or more bacterial strains that directly inhibit a pathogenic
bacterium through production of a secreted product, one or more
strains that directly compete with the pathogenic bacteria for a
niche and/or for nutrients, one or more bacterial strains that
decolonize a pathogenic bacterium, and/or one or more bacterial
strains that eradicate a pathogenic bacterium.
[0127] In some embodiments, the mixtures of bacterial strains treat
or prevent an autoimmune disorder including, but not limited to,
acute disseminated encephalomyelitis (ADEM), acute necrotizing
hemorrhagic leukoencephalitis, Addison's disease,
agammaglobulinemia, alopecia areata, amyloidosis, ankylosing
spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome
(APS), autoimmune angioedema, autoimmune aplastic anemia,
autoimmune dysautonomia, autoimmune hemolytic anemia, autoimmune
hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency,
autoimmune inner ear disease (AIED), autoimmune myocarditis,
autoimmune oophoritis, autoimmune pancreatitis, autoimmune
retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune
thyroid disease, autoimmune urticarial, axonal & neuronal
neuropathies, Balo disease, Behcet's disease, bullous pemphigoid,
cardiomyopathy, Castleman disease, celiac disease, Chagas disease,
chronic inflammatory demyelinating polyneuropathy (CIDP), chronic
recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome,
cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease,
Cogan's syndrome, cold agglutinin disease, congenital heart block,
Coxsackie myocarditis, CREST disease, essential mixed
cryoglobulinemia, demyelinating neuropathies, dermatitis
herpetiformis, dermatomyositis, Devic's disease (neuromyelitis
optica), discoid lupus, Dressler's syndrome, endometriosis,
eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum,
experimental allergic encephalomyelitis, Evans syndrome, fibrosing
alveolitis, giant cell arteritis (temporal arteritis), giant cell
myocarditis, glomerulonephritis, Goodpasture's syndrome,
granulomatosis with polyangiitis (GPA), Graves' disease,
Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's
thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes
gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic
purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,
immunoregulatory lipoproteins, inclusion body myositis,
interstitial cystitis, juvenile arthritis, juvenile idiopathic
arthritis, juvenile myositis, Kawasaki syndrome, Lambert-Eaton
syndrome, leukocytoclastic vasculitis, lichen planus, lichen
sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus
(systemic lupus erythematosus), chronic Lyme disease, Meniere's
disease, microscopic polyangiitis, mixed connective tissue disease
(MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple
sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis
optica (Devic's), neutropenia, ocular cicatricial pemphigoid, optic
neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcus),
paraneoplastic cerebellar degeneration, paroxysmal nocturnal
hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner
syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral
neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS
syndrome, polyarteritis nodosa, type I, II, & Ill autoimmune
polyglandular syndromes, polymyalgia rheumatic, polymyositis,
postmyocardial infarction syndrome, postpericardiotomy syndrome,
progesterone dermatitis, primary biliary cirrhosis, primary
sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic
pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia,
Raynaud's phenomenon, reactive arthritis, reflex sympathetic
dystrophy, Reiter's syndrome, relapsing polychondritis, restless
legs syndrome, retroperitoneal fibrosis, rheumatic fever,
rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,
scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity,
stiff person syndrome, subacute bacterial endocarditis (SBE),
Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis,
temporal arteritis/giant cell arteritis, thrombocytopenic purpura
(TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes,
asthma, ulcerative colitis, undifferentiated connective tissue
disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis,
vitiligo, and Wegener's granulomatosis.
[0128] In embodiments, the mixtures of bacterial strains treat or
prevent diseases or disorders relating to the "gut-brain axis",
including neurodegenerative, neurodevelopmental and neurocognitive
disorders, such as anorexia, anxiety, autism-spectrum disorder,
depression, Parkinson's, and Schizophrenia.
[0129] In embodiments, the mixtures of bacterial strains treat,
prevent, or reduce a side effect of an anti-cancer therapy and/or
increase efficacy of an anti-cancer therapeutic agent and/or
anti-cancer therapy.
[0130] In embodiments, the anti-cancer therapy is surgery,
radiation therapy, chemotherapy (including hormonal therapy) and/or
targeted therapy (including an immunotherapy). Illustrative
chemotherapeutics agents are provided elsewhere herein. In
embodiments, the immunotherapy binds to and/or recognizes a
tumor-cell antigen and/or a cancer-cell antigen, e.g., CTLA-4,
PD-1, PD-L1, or PD-L2. In embodiments, the immunotherapy comprises
administration of Keytruda (Pembrolizumab), Opdivo (Nivolumab),
Yervoy (Ipilimumab), Tecentriq (atezolizumab), Bavencio (avelumab),
and Imfinzi (durvalumab).
[0131] In embodiments, the subject, e.g., a human, is refractory
and/or non-responsive to an anti-cancer therapy (as described
herein). In embodiments, the pharmaceutical composition treats a
subject that presents a non-curative response, a limited response,
or no response to the anti-cancer therapy, or even progress, after
12 weeks or so of receiving the anti-cancer therapy. Thus, a
pharmaceutical composition of the present invention can rescue
subjects that are refractory and/or non-responsive to the
anti-cancer therapy. In embodiments, the subject is refractory
and/or non-responsive to a treatment directed to a checkpoint
molecule, e.g., CTLA-4, PD-1, PD-L1, and/or PD-L2. In embodiments,
the treatment directed to a checkpoint molecule comprises
administration of Keytruda (Pembrolizumab), Opdivo (Nivolumab),
Yervoy (Ipilimumab), Tecentriq (atezolizumab), Bavencio (avelumab),
or lmfinzi (durvalumab).
[0132] Cancers or tumors refer to an uncontrolled growth of cells
and/or abnormal increased cell survival and/or inhibition of
apoptosis which interferes with the normal functioning of the
bodily organs and systems. Included are benign and malignant
cancers, polyps, hyperplasia, as well as dormant tumors or
micrometastases. Also, included are cells having abnormal
proliferation that is not impeded by the immune system (e.g., virus
infected cells). The cancer may be a primary cancer or a metastatic
cancer. The primary cancer may be an area of cancer cells at an
originating site that becomes clinically detectable, and may be a
primary tumor. In contrast, the metastatic cancer may be the spread
of a disease from one organ or part to another non-adjacent organ
or part. The metastatic cancer may be caused by a cancer cell that
acquires the ability to penetrate and infiltrate surrounding normal
tissues in a local area, forming a new tumor, which may be a local
metastasis. The cancer may also be caused by a cancer cell that
acquires the ability to penetrate the walls of lymphatic and/or
blood vessels, after which the cancer cell is able to circulate
through the bloodstream (thereby being a circulating tumor cell) to
other sites and tissues in the body. The cancer may be due to a
process such as lymphatic or hematogeneous spread. The cancer may
also be caused by a tumor cell that comes to rest at another site,
re-penetrates through the vessel or walls, continues to multiply,
and eventually forms another clinically detectable tumor. The
cancer may be this new tumor, which may be a metastatic (or
secondary) tumor.
[0133] The cancer may be caused by tumor cells that have
metastasized, which may be a secondary or metastatic tumor. The
cells of the tumor may be like those in the original tumor. As an
example, if a breast cancer or colon cancer metastasizes to the
liver, the secondary tumor, while present in the liver, is made up
of abnormal breast or colon cells, not of abnormal liver cells. The
tumor in the liver may thus be a metastatic breast cancer or a
metastatic colon cancer, not liver cancer.
[0134] The cancer may have an origin from any tissue. The cancer
may originate from melanoma, colon, breast, or prostate, and thus
may be made up of cells that were originally skin, colon, breast,
or prostate, respectively. The cancer may also be a hematological
malignancy, which may be leukemia or lymphoma. The cancer may
invade a tissue such as liver, lung, bladder, or intestinal.
[0135] Representative cancers and/or tumors of the present
invention include, but are not limited to, a basal cell carcinoma,
biliary tract cancer; bladder cancer; bone cancer; brain and
central nervous system cancer; breast cancer (including
Triple-Negative Breast Cancer); cancer of the peritoneum; cervical
cancer; choriocarcinoma; colon and rectum cancer; connective tissue
cancer; cancer of the digestive system; endometrial cancer;
esophageal cancer; eye cancer; cancer of the head and neck; gastric
cancer (including gastrointestinal cancer); glioblastoma; hepatic
carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal
cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.,
small-cell lung cancer, non-small cell lung cancer, adenocarcinoma
of the lung, and squamous carcinoma of the lung); melanoma;
myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and
pharynx); ovarian cancer; pancreatic cancer; prostate cancer;
retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the
respiratory system; salivary gland carcinoma; sarcoma; skin cancer;
squamous cell cancer; stomach cancer; testicular cancer; thyroid
cancer; uterine or endometrial cancer; cancer of the urinary
system; urothelial carcinoma, vulval cancer; lymphoma including
Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma
(including low grade/follicular non-Hodgkin's lymphoma (NHL); small
lymphocytic (SL) NHL; intermediate grade/follicular NHL;
intermediate grade diffuse NHL; high grade immunoblastic NHL; high
grade lymphoblastic NHL; high grade small non-cleaved cell NHL;
bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and
Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia
(CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia;
chronic myeloblastic leukemia; as well as other carcinomas and
sarcomas; and post-transplant lymphoproliferative disorder (PTLD),
as well as abnormal vascular proliferation associated with
phakomatoses, edema (such as that associated with brain tumors),
and Meigs' syndrome.
[0136] In various embodiments, the mixtures of bacterial strains
may stimulate and/or activate Toll-like receptor activity (e.g.,
TLR1, and/or TLR2, and/or TLR3, and/or TLR4, and/or TLR5, and/or
TLR6, and/or TLR7, and/or TLR8, and/or TLR9, and/or TLR10, and/or
TLR11, and/or TLR12, and/or TLR13).
[0137] In some embodiments, the mixtures of bacterial strains treat
or prevent a diarrheal disease including, but not limited to, acute
bloody diarrhea (e.g., dysentery), acute watery diarrhea (e.g.,
cholera), checkpoint inhibitor-associated colitis, diarrhea due to
food poisoning, persistent diarrhea, and traveler's diarrhea.
[0138] In some embodiments, the mixtures of bacterial strains treat
or prevent an IBD or related disease including, but not limited to,
Behcet's disease, collagenous colitis, Crohn's disease, diversion
colitis, fulminant colitis, intermediate colitis, left-sided
colitis, lymphocytic colitis, pancolitis, pouchitis,
proctosigmoiditis, short bowel syndrome, ulcerative colitis, and
ulcerative proctitis.
[0139] In some embodiments, the mixtures of bacterial strains treat
or prevent the various GI disorders disclosed herein and/or as
known in the art to be a result of gut dysbiosis.
[0140] In some embodiments the mixtures of bacterial strains reduce
GI immunoactivation and inflammation.
[0141] In various embodiments, the mixtures of bacterial strains
treat or prevent various bloodstream infections (BSI).
[0142] In some embodiments, the mixtures of bacterial strains treat
or prevent catheter or intravascular-line infections (e.g.,
central-line infections).
[0143] In some embodiments, the mixtures of bacterial strains treat
or prevent chronic inflammatory diseases.
[0144] In some embodiments, the mixtures of bacterial strains treat
or prevent meningitis.
[0145] In some embodiments, the mixtures of bacterial strains treat
or prevent pneumonia, e.g., ventilator-associated pneumonia.
[0146] In some embodiments, the mixtures of bacterial strains treat
or prevent skin and soft tissue infections.
[0147] In some embodiments, the mixtures of bacterial strains treat
or prevent surgical-site infections.
[0148] In some embodiments, the mixtures of bacterial strains treat
or prevent urinary tract infections (e.g., antibiotic-resistant
urinary tract infections and catheter-associated urinary tract
infections).
[0149] In some embodiments, the mixtures of bacterial strains treat
or prevent wound infections
[0150] In embodiments, the mixtures of bacterial strains treat or
prevent other well-known infections: antibiotic-resistant
infections and antibiotic-sensitive infections.
[0151] In various embodiments, the mixture of bacterial strains
includes one or more bacterial strains that interact
synergistically for treating or preventing a herein-described
disorder, disease, or disorder.
[0152] In some embodiments, the mixtures of bacterial strains
reduce, ameliorate, or eliminate one or more symptom(s) associated
with a herein-described disease, disorder, or condition. Exemplary
symptoms include, but are not limited to, diarrhea, bloody stool,
mouth sores, perianal disease, abdominal pain, abdominal cramping,
fever, fatigue, weight loss, iron deficiency, anemia, appetite
loss, weight loss, anorexia, delayed growth, delayed pubertal
development, and inflammation of the skin, eyes, joints, liver, and
bile ducts.
[0153] In some embodiments, the pharmaceutical composition of the
invention comprises a bacterial strain derived from any one of the
phylum, class, order, family, genus, and/or species listed in Table
5 or Table 6. In exemplary embodiments, the pharmaceutical
composition of the invention comprises a bacterial strain belonging
to the phylum Bacteroidetes or Firmicutes. In exemplary
embodiments, the pharmaceutical composition of the invention
comprises a bacterial strain belonging to the class Clostridia,
Bacteroidia, or Bacilli. In exemplary embodiments, the
pharmaceutical composition of the invention comprises a bacterial
strain belonging to the order Bacteroidales, Clostridiales, or
Lactobacillales. In exemplary embodiments, the pharmaceutical
composition of the invention comprises a bacterial strain belonging
to the family Bacteroidaceae, Ruminococcaceae, Lachnospiraceae, or
Streptococcacea. In exemplary embodiments, the pharmaceutical
composition of the invention comprises a bacterial strain belonging
to the genus Bacteroides, Blautia, Faecalibacterium, Coprococcus,
Roseburia, Dorea, Clostridium, Eubacterium or Streptococcus. In
exemplary embodiments, the pharmaceutical composition of the
invention comprises a bacterial strain belonging to the species
uniformis, prausnitzii, or faecis.
[0154] Pharmaceutical Compositions, Formulations, and
Administration
[0155] The present invention provides pharmaceutical compositions
comprising the novel mixtures of bacterial strains (and/or
additional therapeutic agents) in various formulations. Any
pharmaceutical composition (and/or additional therapeutic agents)
described herein can take the form of tablets, pills, pellets,
capsules, capsules containing liquids, capsules containing
multiparticulates, powders, solutions, emulsion, drops,
suppositories, emulsions, aerosols, sprays, suspensions,
delayed-release formulations, sustained-release formulations,
controlled-release formulations, or any other form suitable for
use.
[0156] The formulations comprising the pharmaceutical compositions
(and/or additional therapeutic agents) may conveniently be
presented in unit dosage forms. For example, the dosage forms may
be prepared by methods which include the step of bringing the
therapeutic agents into association with a carrier, which
constitutes one or more accessory ingredients. For example, the
formulations are prepared by uniformly and intimately bringing the
therapeutic agent into association with a liquid carrier, a finely
divided solid carrier, or both, and then, if necessary, shaping the
product into dosage forms of the desired formulation (e.g., wet or
dry granulation, powder blends, etc., followed by press
tableting).
[0157] In one embodiment, the pharmaceutical compositions
comprising the novel mixtures of bacterial strains (and/or
additional therapeutic agents) described herein are formulated as a
composition adapted for a mode of administration described
herein.
[0158] In various embodiments, the administration of the
pharmaceutical compositions (and/or additional therapeutic agents)
is any one of oral, intravenous, intraperitoneal, and parenteral.
For example, routes of administration include, but are not limited
to, oral, intraperitoneal, intravenous, intramuscular, or rectally.
In various embodiments, the administration of the pharmaceutical
compositions (and/or additional therapeutic agents) is oral,
naso-gastric, anterograde gastrointestinal, retrograde
gastrointestinal, endoscopic, or enemic.
[0159] In one embodiment, the pharmaceutical compositions (and/or
additional therapeutic agents) described herein are formulated as a
composition adapted for oral administration. Compositions for oral
delivery can be in the form of tablets, aqueous or oily
suspensions, granules, powders, sprinkles, emulsions, or capsules
as examples. Orally administered compositions can comprise one or
more agents, for example, sweetening agents such as fructose,
aspartame or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry; coloring agents; perfuming agents, to mask
an odor of a bacterial mixture; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, when in capsule,
tablet, or pill form, the compositions can be coated to delay
disintegration to provide a sustained action over an extended
period of time. Selectively permeable membranes surrounding an
osmotically active agent driving any microbial strain (and/or
additional therapeutic agents) described herein are also suitable
for orally administered compositions. In these latter platforms,
fluid from the environment surrounding the capsule is imbibed by
the driving compound, which swells to displace the agent or agent
composition through an aperture. These delivery platforms can
provide an essentially zero order delivery profile as opposed to
the spiked profiles of immediate release formulations. A time-delay
material such as glycerol monostearate or glycerol stearate can
also be useful. Oral compositions can include standard excipients
such as mannitol, lactose, starch, magnesium stearate, sodium
saccharin, cellulose, ethacrylic acid and derivative polymers
thereof, and magnesium carbonate. In one embodiment, the excipients
are of pharmaceutical grade. Suspensions, in addition to the active
compounds, may contain suspending agents such as, for example,
ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures
thereof.
[0160] Oral administration of the pharmaceutical compositions
comprising bacterial mixtures, e.g., via a capsule, is preferable
since this route is simpler and more convenient than more
conventional, invasive techniques like enema, nasogastric tube, or
colonoscopy.
[0161] In various embodiments, the pharmaceutical compositions
(and/or additional therapeutic agent) are formulated as solid
dosage forms such as tablets, dispersible powders, granules, and
capsules. In one embodiment, the pharmaceutical compositions
(and/or additional therapeutic agent) are formulated as a capsule.
In another embodiment, the pharmaceutical compositions (and/or
additional therapeutic agent) are formulated as a capsule or
tablet. In yet another embodiment, the pharmaceutical compositions
(and/or additional therapeutic agent) are formulated as a soft-gel
capsule. In a further embodiment, the pharmaceutical compositions
(and/or additional therapeutic agent) are formulated as a gelatin
capsule.
[0162] Dosage forms suitable for parenteral administration (e.g.,
intravenous, intramuscular, or intraperitoneal injection and
infusion) include, for example, solutions, suspensions,
dispersions, emulsions, and the like. They may also be manufactured
in the form of sterile solid compositions (e.g., lyophilized
composition), which can be dissolved or suspended in sterile
injectable medium immediately before use. They may contain, for
example, suspending or dispersing agents.
[0163] In various embodiments, the formulations of the invention
may additionally comprise a pharmaceutically acceptable carrier or
excipient. As one skilled in the art will recognize, the
formulations can be in any suitable form appropriate for the
desired use and route of administration.
[0164] In some dosage forms, the agents described herein can be
mixed with at least one inert, pharmaceutically acceptable
excipient or carrier such as sodium citrate, dicalcium phosphate,
and/or (a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, silicic acid, microcrystalline cellulose, and
Bakers Special Sugar, (b) binders such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,
sucrose, acacia, polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl
cellulose etc., (c) humectants such as glycerol, (d) disintegrating
agents such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, sodium carbonate,
cross-linked polymers such as crospovidone (cross-linked polyvinyl
pyrrolidone), croscarmellose sodium (cross-linked sodium
carboxymethylcellulose), sodium starch glycolate, (e) solution
retarding agents such as paraffin, (f) absorption accelerators such
as quaternary ammonium compounds, (g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, (h) absorbents
such as kaolin and bentonite clay, and (i) lubricants such as talc,
calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate, glyceryl behenate, and mixtures of such
excipients. One of skill in the art will recognize that particular
excipients may have two or more functions in the oral dosage form.
In the case of an oral dosage form, for example, a capsule or a
tablet, the dosage form may also comprise buffering agents.
[0165] The formulation can additionally include a surface active
agent. Surface active agents suitable for use in the present
invention include, but are not limited to, any pharmaceutically
acceptable, non-toxic surfactant. Classes of surfactants suitable
for use in the compositions of the invention include, but are not
limited to polyethoxylated fatty acids, PEG-fatty acid diesters,
PEG-fatty acid mono- and di-ester mixtures, polyethylene glycol
glycerol fatty acid esters, alcohol-oil transesterification
products, polyglycerized fatty acids, propylene glycol fatty acid
esters, mixtures of propylene glycol esters-glycerol esters, mono-
and diglycerides, sterol and sterol derivatives, polyethylene
glycol sorbitan fatty acid esters, polyethylene glycol alkyl
ethers, sugar esters, polyethylene glycol alkyl phenols,
polyoxyethylene-olyoxypropylene block copolymers, sorbitan fatty
acid esters, lower alcohol fatty acid esters, ionic surfactants,
and mixtures thereof. In some embodiments, compositions of the
invention may comprise one or more surfactants including, but not
limited to, sodium lauryl sulfate, polysorbate 20, polysorbate 40,
polysorbate 60, polysorbate 80, and triethyl citrate.
[0166] The formulation can also contain pharmaceutically acceptable
plasticizers to obtain the desired mechanical properties such as
flexibility and hardness. Such plasticizers include, but are not
limited to, triacetin, citric acid esters, triethyl citrate,
phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene
glycols, polysorbates or other plasticizers.
[0167] The formulation can also include one or more application
solvents. Some of the more common solvents that can be used to
apply, for example, a delayed-release coating composition include
isopropyl alcohol, acetone, methylene chloride and the like.
[0168] The formulation can also include one or more alkaline
materials. Alkaline material suitable for use in compositions of
the invention include, but are not limited to, sodium, potassium,
calcium, magnesium and aluminum salts of acids such as phosphoric
acid, carbonic acid, citric acid and other aluminum/magnesium
compounds. In addition, the alkaline material may be selected from
antacid materials such as aluminum hydroxides, calcium hydroxides,
magnesium hydroxides and magnesium oxide.
[0169] In various embodiments, the pharmaceutical compositions
(and/or additional therapeutic agents) are formulated for systemic
or local delivery. In an embodiment, administration is systemic. In
another embodiment, it may be desirable to administer locally to
the area in need of treatment.
[0170] Various methods may be used to formulate and/or deliver the
agents described herein to a location of interest. For example, the
pharmaceutical compositions (and/or additional therapeutic agents)
described herein may be formulated for delivery to the GI tract.
The GI tract includes organs of the digestive system such as mouth,
esophagus, stomach, duodenum, small intestine, large intestine
(also referred here to as the "colon") and rectum and includes all
subsections thereof (e.g., the small intestine may include the
duodenum, jejunum and ileum; the large intestine may include the
colon transversum, colon descendens, colon ascendens, colon
sigmoidenum and cecum). For example, the bacterial strains and/or
pharmaceutical compositions (and/or additional therapeutic agents)
described herein may be formulated for delivery to one or more of
the stomach, small intestine, large intestine and rectum and
includes all subsections thereof (e.g., duodenum, jejunum and
ileum, colon transversum, colon descendens, colon ascendens, colon
sigmoidenum and cecum). In some embodiments, the compositions
described herein may be formulated to deliver to the upper or lower
GI tract. In an embodiment, the bacterial strains and/or
pharmaceutical compositions (and/or additional therapeutic agents)
may be administered to a subject, by, for example, directly or
indirectly contacting the mucosal tissues of the GI tract.
[0171] In various embodiments, the administration the
pharmaceutical compositions (and/or additional therapeutic agents)
is into the GI tract via, for example, oral delivery, nasogastric
tube, intestinal intubation (e.g., an enteral tube or feeding tube
such as, for example, a jejunal tube or gastro-jejunal tube, etc.),
direct infusion (e.g., duodenal infusion), endoscopy, colonoscopy,
or enema.
[0172] In various embodiments, the administration the
pharmaceutical compositions (and/or additional therapeutic agents)
is into the female reproductive system, for example by vaginal
delivery, e.g., as vaginal suppository.
[0173] For example, in various embodiments, the present invention
provides modified-release formulations comprising the novel
mixtures of bacterial strains (and/or additional therapeutic
agents), wherein the formulation releases a substantial amount of
the bacterial strains (and/or additional therapeutic agents) into
one or more regions of the GI tract. For example, the formulation
may release at least about 60% of the bacterial strains after the
stomach and into one or more regions of the GI tract.
[0174] In various embodiments, the modified-release formulation of
the present invention releases at least 60% of the bacterial
strains (or additional therapeutic agents) after the stomach into
one or more regions of the intestine. For example, the
modified-release formulation releases at least 60%, at least 61%,
at least 62%, at least 63%, at least 64%, at least 65%, at least
66%, at least 67%, at least 68%, at least 69%, at least 70%, at
least 71%, at least 72%, at least 73%, at least 74%, at least 75%,
at least 76%, at least 77%, at least 78%, at least 79%, at least
80%, at least 81%, at least 82%, at least 83%, at least 84%, at
least 85%, at least 86%, at least 87%, at least 88%, at least 89%,
at least 90%, at least 91%, at least 92%, at least 93%, at least
94%, at least 95%, at least 96%, at least 97%, at least 98%, at
least 99%, or 100% of the bacterial strains (or additional
therapeutic agents) in the intestines.
[0175] In various embodiments, the modified-release formulation of
the present invention releases at least 60% of the bacterial
strains (or additional therapeutic agents) in the small intestine.
For example, the modified-release formulation releases at least
60%, at least 61%, at least 62%, at least 63%, at least 64%, at
least 65%, at least 66%, at least 67%, at least 68%, at least 69%,
at least 70%, at least 71%, at least 72%, at least 73%, at least
74%, at least 75%, at least 76%, at least 77%, at least 78%, at
least 79%, at least 80%, at least 81%, at least 82%, at least 83%,
at least 84%, at least 85%, at least 86%, at least 87%, at least
88%, at least 89%, at least 90%, at least 91%, at least 92%, at
least 93%, at least 94%, at least 95%, at least 96%, at least 97%,
at least 98%, at least 99%, or 100% of the bacterial strains (or
additional therapeutic agents) in the small intestine (e.g., one or
more of duodenum, jejunum, ileum, and ileocecal junction).
[0176] In various embodiments, the modified-release formulation of
the present invention releases at least 60% of the bacterial
strains (or additional therapeutic agents) in the large intestine.
For example, the modified-release formulation releases at least
60%, at least 61%, at least 62%, at least 63%, at least 64%, at
least 65%, at least 66%, at least 67%, at least 68%, at least 69%,
at least 70%, at least 71%, at least 72%, at least 73%, at least
74%, at least 75%, at least 76%, at least 77%, at least 78%, at
least 79%, at least 80%, at least 81%, at least 82%, at least 83%,
at least 84%, at least 85%, at least 86%, at least 87%, at least
88%, at least 89%, at least 90%, at least 91%, at least 92%, at
least 93%, at least 94%, at least 95%, at least 96%, at least 97%,
at least 98%, at least 99%, or 100% of the bacterial strains (or
additional therapeutic agents) in the large intestine (e.g., one or
more of cecum, ascending, transverse, descending or sigmoid
portions of the colon, and rectum).
[0177] In various embodiments, the pharmaceutical composition is
formulated for substantially complete delivery prior to the
rectum.
[0178] In some embodiments, the pharmaceutical composition is
formulated for release in the stomach (e.g., so-called reverse
enteric formulations). In other embodiments, the pharmaceutical
composition is formulated so as to not substantially release the
bacterial strains in the stomach.
[0179] In certain embodiments, the modified-release formulation
releases the bacterial strains (or additional therapeutic agents)
at a specific pH. For example, in some embodiments, the
modified-release formulation is substantially stable in an acidic
environment and substantially unstable (e.g., dissolves rapidly or
is physically unstable) in a near neutral to alkaline environment.
In some embodiments, stability is indicative of not substantially
releasing while instability is indicative of substantially
releasing. For example, in some embodiments, the modified-release
formulation is substantially stable at a pH of about 7.0 or less,
or about 6.5 or less, or about 6.0 or less, or about 5.5 or less,
or about 5.0 or less, or about 4.5 or less, or about 4.0 or less,
or about 3.5 or less, or about 3.0 or less, or about 2.5 or less,
or about 2.0 or less, or about 1.5 or less, or about 1.0 or less.
In some embodiments, the present formulations are stable in lower
pH areas and therefore do not substantially release in, for
example, the stomach. In some embodiments, modified-release
formulation is substantially stable at a pH of about 1 to about 4
or lower and substantially unstable at pH values that are greater.
In these embodiments, the modified-release formulation does not
substantially release in the stomach. In these embodiments, the
modified-release formulation substantially releases in the small
intestine (e.g., one or more of the duodenum, jejunum, and ileum)
and/or large intestine (e.g., one or more of the cecum, ascending
colon, transverse colon, descending colon, and sigmoid colon). In
some embodiments, modified-release formulation is substantially
stable at a pH of about 4 to about 5 or lower and consequentially
is substantially unstable at pH values that are greater and
therefore is not substantially released in the stomach and/or small
intestine (e.g., one or more of the duodenum, jejunum, and ileum).
In these embodiments, the modified-release formulation
substantially releases in the large intestine (e.g., one or more of
the cecum, ascending colon, transverse colon, descending colon, and
sigmoid colon). In various embodiments, the pH values recited
herein may be adjusted as known in the art to account for the state
of the subject, e.g., whether in a fasting or postprandial
state.
[0180] In some embodiments, the modified-release formulation is
substantially stable in gastric fluid and substantially unstable in
intestinal fluid and, accordingly, is substantially released in the
small intestine (e.g., one or more of the duodenum, jejunum, and
ileum) and/or large intestine (e.g., one or more of the cecum,
ascending colon, transverse colon, descending colon, and sigmoid
colon).
[0181] In some embodiments, the modified-release formulation is
stable in gastric fluid or stable in acidic environments. These
modified-release formulations release about 30% or less by weight
of the bacterial strains and/or additional therapeutic agent in the
modified-release formulation in gastric fluid with a pH of about 4
to about 5 or less, or simulated gastric fluid with a pH of about 4
to about 5 or less, in about 15, or about 30, or about 45, or about
60, or about 90 minutes. Modified-release formulations of the of
the invention may release from about 0% to about 30%, from about 0%
to about 25%, from about 0% to about 20%, from about 0% to about
15%, from about 0% to about 10%, about 5% to about 30%, from about
5% to about 25%, from about 5% to about 20%, from about 5% to about
15%, from about 5% to about 10% by weight of the bacterial strains
and/or additional therapeutic agent in the modified-release
formulation in gastric fluid with a pH of 4-5, or less or simulated
gastric fluid with a pH of 4-5 or less, in about 15, or about 30,
or about 45, or about 60, or about 90 minutes. Modified-release
formulations of the invention may release about 1%, about 2%, about
3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or
about 10% by weight of the total bacterial strains and/or
additional therapeutic agent in the modified-release formulation in
gastric fluid with a pH of 5 or less, or simulated gastric fluid
with a pH of 5 or less, in about 15, or about 30, or about 45, or
about 60, or about 90 minutes.
[0182] In some embodiments, the modified-release formulation is
unstable in intestinal fluid. These modified-release formulations
release about 70% or more by weight of the bacterial strains and/or
additional therapeutic agent in the modified-release formulation in
intestinal fluid or simulated intestinal fluid in about 15, or
about 30, or about 45, or about 60, or about 90 minutes. In some
embodiments, the modified-release formulation is unstable in near
neutral to alkaline environments. These modified-release
formulations release about 70% or more by weight of the bacterial
strains and/or additional therapeutic agent in the modified-release
formulation in intestinal fluid with a pH of about 4-5 or greater,
or simulated intestinal fluid with a pH of about 4-5 or greater, in
about 15, or about 30, or about 45, or about 60, or about 90
minutes. A modified-release formulation that is unstable in near
neutral or alkaline environments may release 70% or more by weight
of bacterial strains and/or additional therapeutic agent in the
modified-release formulation in a fluid having a pH greater than
about 5 (e.g., a fluid having a pH of from about 5 to about 14,
from about 6 to about 14, from about 7 to about 14, from about 8 to
about 14, from about 9 to about 14, from about 10 to about 14, or
from about 11 to about 14) in from about 5 minutes to about 90
minutes, or from about 10 minutes to about 90 minutes, or from
about 15 minutes to about 90 minutes, or from about 20 minutes to
about 90 minutes, or from about 25 minutes to about 90 minutes, or
from about 30 minutes to about 90 minutes, or from about 5 minutes
to about 60 minutes, or from about 10 minutes to about 60 minutes,
or from about 15 minutes to about 60 minutes, or from about 20
minutes to about 60 minutes, or from about 25 minutes to about 90
minutes, or from about 30 minutes to about 60 minutes.
[0183] Examples of simulated gastric fluid and simulated intestinal
fluid include, but are not limited to, those disclosed in the 2005
Pharmacopeia 23NF/28USP in Test Solutions at page 2858 and/or other
simulated gastric fluids and simulated intestinal fluids known to
those of skill in the art, for example, simulated gastric fluid
and/or intestinal fluid prepared without enzymes.
[0184] In various embodiments, the modified-release formulation of
the invention is substantially stable in chyme. For example, there
is, in some embodiments, a loss of less about 50% or about 40%, or
about 30%, or about 20%, or about 10% of bacterial strains activity
in about 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1
hour from administration.
[0185] In various embodiments, the modified-release formulations of
the present invention are designed for immediate release (e.g.,
upon ingestion). In various embodiments, the modified-release
formulations may have sustained-release profiles, i.e., slow
release of the active ingredient(s) in the body (e.g., GI tract)
over an extended period of time. In various embodiments, the
modified-release formulations may have a delayed-release profile,
i.e., not immediately release the active ingredient(s) upon
ingestion; rather, postponement of the release of the active
ingredient(s) until the composition is lower in the GI tract; for
example, for release in the small intestine (e.g., one or more of
duodenum, jejunum, ileum) or the large intestine (e.g., one or more
of cecum, ascending, transverse, descending or sigmoid portions of
the colon, and rectum). For example, a composition can be enteric
coated to delay release of the active ingredient(s) until it
reaches the small intestine or large intestine.
[0186] In various embodiments, the modified-release formulation of
the present invention may utilize one or more modified-release
coatings such as delayed-release coatings to provide for effective,
delayed yet substantial delivery of the bacterial strains to the GI
tract together with, optionally, additional therapeutic agents.
[0187] In one embodiment, the delayed-release coating includes an
enteric agent that is substantially stable in acidic environments
and substantially unstable in near neutral to alkaline
environments. In an embodiment, the delayed-release coating
contains an enteric agent that is substantially stable in gastric
fluid. The enteric agent can be selected from, for example,
solutions or dispersions of methacrylic acid copolymers, cellulose
acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate,
polyvinyl acetate phthalate, carboxymethylethylcellulose, and
EUDRAGIT.RTM.-type polymer (poly(methacrylic acid,
methylmethacrylate), hydroxypropyl methylcellulose acetate
succinate, cellulose acetate trimellitate, hypromellose (INN)
hydroxypropyl methylcellulose (HPMC), shellac or other suitable
enteric coating polymers. Similar polymers include Kollicoat.RTM.
MAE 30 DP and Kollicoat.RTM. MAE 100 P. In various embodiments, the
enteric agent may be a combination of the foregoing solutions or
dispersions. In embodiments, the enteric agent comprises any
EUDRAGIT.RTM.-type polymer, derivatives thereof, and copolymers
thereof. EUDRAGIT.RTM. polymers are available from Evonik
Industries AG (Essen, Germany).
[0188] In certain embodiments, one or more coating system additives
are used with the enteric agent. For example, one or more
PlasACRYL.TM. additives may be used as an anti-tacking agent
coating additive. Illustrative PlasACRYL.TM. additives include, but
are not limited to PlasACRYL.TM. HTP20 and PlasACRYL.TM. T20.
[0189] In another embodiment, the delayed-release coating may
degrade as a function of time when in aqueous solution without
regard to the pH and/or presence of enzymes in the solution. Such a
coating may comprise a water insoluble polymer. Its solubility in
aqueous solution is therefore independent of the pH. The term "pH
independent" as used herein means that the water permeability of
the polymer and its ability to release pharmaceutical ingredients
is not a function of pH and/or is only very slightly dependent on
pH. Such coatings may be used to prepare, for example, sustained
release formulations. Suitable water insoluble polymers include
pharmaceutically acceptable non-toxic polymers that are
substantially insoluble in aqueous media, e.g., water, independent
of the pH of the solution. Suitable polymers include, but are not
limited to, cellulose ethers, cellulose esters, or cellulose
ether-esters, i.e., a cellulose derivative in which some of the
hydroxy groups on the cellulose skeleton are substituted with alkyl
groups and some are modified with alkanoyl groups. Examples include
ethyl cellulose, acetyl cellulose, nitrocellulose, and the like.
Other examples of insoluble polymers include, but are not limited
to, lacquer, and acrylic and/or methacrylic ester polymers,
polymers or copolymers of acrylate or methacrylate having a low
quaternary ammonium content, or mixture thereof and the like. Other
examples of insoluble polymers include EUDRAGIT RS.RTM., EUDRAGIT
RL.RTM., and EUDRAGIT NE.RTM.. Insoluble polymers useful in the
present invention include polyvinyl esters, polyvinyl acetals,
polyacrylic acid esters, butadiene styrene copolymers, and the
like. In one embodiment, colonic delivery is achieved by use of a
slowly-eroding wax plug (e.g., various PEGS, including for example,
PEG6000).
[0190] In some embodiments, an enteric (interior or exterior)
coating comprises a polymeric material. Non-limiting examples of
suitable polymeric materials include polymethylmethacrylate,
poly(N,N-dimethylacrylamide), polyoxamer, polyethylene glycol,
polypropylene glycol, polysaccharides (e.g., sucrose, trehalose,
glucose, starches such as tapioca and arrowroot, chitosan,
alginate, guar gum), polyacrylate, polymethacrylate, polyvinyl
alcohol, polyalkylene glycols, polyacrylamide,
polyvinylpyrrolidone, polyurethane, polylactide, lactide/glycolide
copolymer, polycaprolactone, polydioxanones, polyanhydride,
polyhydroxybutyrate, polysiloxane, polytrimethylene carbonate,
polyalkylene glycol, and combinations and/or copolymers
thereof.
[0191] In a further embodiment, the delayed-release coating may be
degraded by a microbial enzyme present in the gut flora. In one
embodiment, the delayed-release coating may be degraded by a
bacteria present in the small intestine. In another embodiment, the
delayed-release coating may be degraded by a bacteria present in
the large intestine.
[0192] Such a coating may comprise a mixture of a first material
which is susceptible to attack by colonic bacteria and a second
material which has a solubility threshold at about pH 5 or above.
The first material may comprise a polysaccharide selected from
starch, amylose, amylopectin, chitosan, chondroitin sulfate,
cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin,
curdulan, and levan. The second material may dissolve in a
pH-dependent manner such that it has a "pH threshold" which is the
pH below which it is insoluble and at or above which it is soluble.
The pH of the surrounding medium triggers dissolution of the second
material; thus, little of the second material dissolves below the
pH threshold. Once the pH of the surrounding medium reaches (or
exceeds) the pH threshold, the second material becomes soluble. In
embodiments, the surrounding medium means the medium in the GI
tract, such as the gastric juice or intestinal juice or the in
vitro equivalent of the medium in the GI tract. The second material
may be a film-forming polymeric material such as an acrylate
polymer, a cellulose polymer or a polyvinyl-based polymer. Examples
of suitable cellulose polymers include cellulose acetate phthalate
("CAP"), cellulose acetate trimellitate ("CAT"), and
hydropropylmethylcellulose acetate succinate. Examples of suitable
polyvinyl-based polymers include polyvinyl acetate phthalate
("PVAP"). The second material may be a co-polymer of a
(meth)acrylic acid and a (meth)acrylic acid C1-4 alkyl ester, for
instance, a copolymer of methacrylic acid and methacrylic acid
methyl ester. Such a polymer is known as a poly(methacrylic
acid/methyl methacrylate) co-polymer. Examples of such co-polymers
are usually anionic and not sustained release polymethacrylates.
Examples of anionic poly(methacrylic acid/methyl methacrylate)
co-polymers include Eudragit.RTM. L, Eudragit.RTM. S, and
Eudragit.RTM. FS. The coating may have an additional layer either
between the bacterial mixture core and the layer comprising the
delayed release composition described above and/or an outer layer
coating the delayed release composition layer as described
above.
[0193] In embodiments, a capsule comprises an interior enteric
coating which has hydrophobic properties which prevents or retards
the contact of an aqueous phase (e.g., a drug substance of the
present disclosure) with the capsule (or capsule material). In
embodiments, the interior enteric coating comprises a hydrophobic
coating. The hydrophobic coating may comprise a material selected
from the group consisting of shellac, zein, polysaccharides, silk,
polycaprolactone, oil, pectin, wax, polymers, shellac, and
derivatives thereof, and combinations thereof. Non-limiting
examples of suitable polysaccharides include alginate, hyaluronic
acid, and chitosan. Non-limiting examples of suitable oils include
avocado oil, vegetable oil, castor oil, olive oil, jojoba oil,
cocoa butter, coconut oil. Non-limiting examples of suitable waxes
include beeswax, carnauba wax, and paraffin wax. In some
embodiments, the hydrophobic coating is shellac.
[0194] An interior enteric coating may be selected and designed
such that it protects the capsule (or capsule material) from an
aqueous phase. For example, in some embodiments, the interior
enteric coating prevents the aqueous phase (e.g., a mixture of
bacterial strains of the present disclosure) from contacting the
capsule and/or such that the capsule material is not degraded
and/or dissolved by the aqueous phase. In some embodiments, the
interior enteric coating protects the capsule from the aqueous
phase for greater than or equal to 1 day, greater than or equal to
2 days, greater than or equal to 3 days, greater than or equal to 7
days, greater than or equal to 14 days, greater than or equal to 30
days, greater than or equal to 90 days, or greater than or equal to
180 days at room temperature under ambient conditions. In certain
embodiments, the interior enteric coating protects the capsule from
the aqueous phase for less than or equal to 365 days, less than or
equal to 180 days, less than or equal to 90 days, less than or
equal to 30 days, less than or equal to 14 days, less than or equal
to 7 days, less than or equal to 3 days, or less than or equal to 2
days at room temperature under ambient conditions. Combinations of
the above-referenced ranges are possible (e.g., greater than or
equal to 1 day and less than or equal to 365 days). Other ranges
are also possible. As such, in some embodiments, the capsule is
stable at room temperature under ambient conditions for the times
listed above (e.g., greater than or equal to 1 day).
[0195] In certain embodiments, the interior enteric coating
protects the capsule from the aqueous phase (e.g., the interior
enteric coating prevents the aqueous phase from contacting the
capsule and/or such that the capsule material is not degraded
and/or dissolved by the aqueous phase) for greater than or equal to
1 hour, greater than or equal to 2 hours, greater than or equal to
3 hours, greater than or equal to 6 hours, greater than or equal to
12 hours, greater than or equal to 18 hours, greater than or equal
to 24 hours, greater than or equal to 48 hours, or greater than or
equal to 96 hours at 37.degree. C. In certain embodiments, the
interior enteric coating protects the capsule from the aqueous
phase for less than or equal to 168 hours, less than or equal to 96
hours, less than or equal to 48 hours, less than or equal to 24
hours, less than or equal to 18 hours, less than or equal to 12
hours, less than or equal to 6 hours, less than or equal to 3
hours, or less than or equal to 2 hours at 37.degree. C. under
ambient conditions. Combinations of the above-referenced ranges are
possible (e.g., greater than or equal to 1 hour and less than or
equal to 168 hours). As such, in certain embodiments, the capsule
is stable at 37.degree. C. under ambient conditions for the times
listed above (e.g., greater than or equal to 1 hour).
[0196] In various embodiments, the modified release formulation is
designed for release in the colon. Various colon-specific delivery
approaches may be utilized. For example, the modified release
formulation may be formulated using a colon-specific drug delivery
system (CODES) as described for example, in Li et al., AAPS
PharmSciTech (2002), 3(4): 1-9, the entire contents of which are
incorporated herein by reference. Drug release in such a system is
triggered by colonic microflora coupled with pH-sensitive polymer
coatings. For example, the formulation may be designed as a core
tablet with three layers of polymer. The first coating is an
acid-soluble polymer (e.g., EUDRAGIT E), the outer coating is
enteric, along with a hydroxypropyl methylcellulose barrier layer
interposed in between. In another embodiment, colon delivery may be
achieved by formulating the bacterial strains (and/or additional
therapeutic agent) with specific polymers that degrade in the colon
such as, for example, pectin. The pectin may be further gelled or
crosslinked with a cation such as a zinc cation. In an embodiment,
the formulation is in the form of ionically crosslinked pectin
beads which are further coated with a polymer (e.g., EUDRAGIT
polymer). Additional colon specific formulations include, but are
not limited to, pressure-controlled drug delivery systems (prepared
with, for example, ethylcellulose) and osmotic controlled drug
delivery systems (i.e., ORDS-CT).
[0197] In some embodiments, an enteric (interior or exterior)
coating comprises an enteric elastomer. In some embodiments, the
enteric elastomer comprises a mixture of two or more polymers with
carboxyl functionality such that the two or more polymers form
hydrogen bonds with one another and has both enteric and elastic
properties. In certain embodiments, the enteric elastomer comprises
a first polymer comprising a structure as in Formula (I):
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein each R.sup.1
is the same or different and is selected from the group consisting
of optionally substituted alkylene, optionally substituted
heteroalkylene, optionally substituted arylene, and optionally
substituted heteroarylene, each R.sup.2 is the same or different
and is selected from the group consisting of hydrogen, optionally
substituted alkyl, and optionally substituted heteroalkyl, each
R.sup.3 is the same or different and is selected from the group
consisting of optionally substituted alkylene and optionally
substituted heteroalkylene, n is an integer between 25 and 250,000,
and a second polymer comprising a structure as in Formula (II)
hydrogen bonded to the first polymer:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein each R.sup.4
is the same or different and is selected from the group consisting
of optionally substituted alkylene and optionally substituted
heteroalkylene, each R.sup.5 is the same or different and is
selected from the group consisting of optionally substituted
alkylene and optionally substituted heteroalkylene, each R.sup.6 is
the same or different and is selected from the group consisting of
hydrogen, optionally substituted alkyl, and optionally substituted
heteroalkyl, each R.sup.7 is the same or different and is selected
from the group consisting of hydrogen, optionally substituted
alkyl, and optionally substituted heteroalkyl, each R.sup.8 is the
same or different and is optionally substituted alkyl, p is an
integer between 1 and 10, q is an integer between 1 and 10, and z
is an integer between 1 and 150,000, provided that (p+q)*z is
greater than or equal to 20. Suitable enteric elastomers and
methods for making such enteric elastomers are described in more
detail in International Patent Publication No. WO2015191922, which
is incorporated herein by reference in its entirety for all
purposes.
[0198] In some embodiments, a capsule comprises a polymeric
material. Non-limiting examples of suitable polymeric materials
include gelatin, polymethylmethacrylate,
poly(N,N-dimethylacrylamide), polyoxamer, polyethylene glycol,
polypropylene glycol, polysaccharides (e.g., sucrose, trehalose,
glucose, starches such as tapioca and arrowroot, chitosan,
alginate, guar gum), polyacrylate, polymethacrylate, polyvinyl
alcohol, polyalkylene glycols, polyacrylamide,
polyvinylpyrrolidone, polyurethane, polylactide, lactide/glycolide
copolymer, polycaprolactone, polydioxanones, polyanhydride,
polyhydroxybutyrate, polysiloxane, polytrimethylene carbonate,
polyalkylene glycol, and combinations and/or copolymers thereof. In
embodiments, the capsule comprises gelatin.
[0199] In certain embodiments, the capsule may comprise a
bioadherent polymer such as mucin.
[0200] Embodiments of dual-coated coated capsules are disclosed in
WO2018057747, the contents of which are incorporated by reference
in their entirety.
[0201] In certain embodiments, the capsule has a particular shape
or size. For example, in some cases, the capsule has a shape or
size as described in the USP including, but not limited to, #000
capsule, #00 capsule, #0 capsule, #1 capsule, #2 capsule, #3
capsule, #4 capsule, or #5 capsule. Other capsule shapes and/or
sizes are also possible.
[0202] Formulations for colon specific delivery of the bacterial
strains (and/or additional therapeutic agents), as described
herein, may be evaluated using, for example, in vitro dissolution
tests. For example, parallel dissolution studies in different
buffers may be undertaken to characterize the behavior of the
formulations at different pH levels. Alternatively, in vitro
enzymatic tests may be carried out. For example, the formulations
may be incubated in fermenters containing suitable medium for
bacteria, and the amount of drug released at different time
intervals is determined. Drug release studies can also be done in
buffer medium containing enzymes or rat or guinea pig or rabbit
cecal contents and the amount of drug released in a particular time
is determined. In a further embodiment, in vivo evaluations may be
carried out using animal models such as dogs, guinea pigs, rats,
and pigs. Further, clinical evaluation of colon specific drug
delivery formulations may be evaluated by calculating drug delivery
index (DDI) which considers the relative ratio of RCE (relative
colonic tissue exposure to the drug) to RSC (relative amount of
drug in blood i.e., that is relative systemic exposure to the
drug). Higher drug DDI indicates better colon drug delivery.
Absorption of drugs from the colon may be monitored by colonoscopy
and intubation.
[0203] In various embodiments, the present formulation provides for
substantial uniform dissolution of the bacterial strains (and/or
additional therapeutic agent) in the area of release in the GI
tract. In an embodiment, the present formulation minimizes patchy
or heterogeneous release of the bacterial strains.
[0204] In various embodiments, the present formulations provide for
release of multiple doses of the bacterial strains along the GI
tract. For example, the composition and/or formulation can release
multiple doses of the bacterial strains at different locations
along the intestines, at different times, and/or at different pH.
The overall release profile of such a formulation may be adjusted
using, for example, multiple particle types or multiple layers. For
example, in one embodiment, the first dose of the bacterial strains
may be formulated for release in, for example, the small intestine
(e.g., one or more of duodenum, jejunum, ileum), whereas the second
dose is formulated for delayed release in, for example, the large
intestines (e.g., one or more of cecum, ascending, transverse,
descending or sigmoid portions of the colon, and rectum). In
another example, the first dose of the bacterial strains may be
formulated for release in, for example, the small intestine (e.g.,
one or more of duodenum, jejunum, ileum), whereas the second dose
is formulated for delayed release in, for example, another part of
the small intestine (e.g., one or more of duodenum, jejunum,
ileum). In another embodiment, the first dose of the bacterial
strains may be formulated for release in, for example, the large
intestine (e.g., one or more of cecum, ascending, transverse,
descending or sigmoid portions of the colon, and rectum), whereas
the second dose is formulated for delayed release in, for example,
another part of the large intestine (e.g., one or more of cecum,
ascending, transverse, descending or sigmoid portions of the colon,
and rectum). In various embodiments, the composition and/or
formulation may release at least one dose, at least two doses, at
least three doses, at least four doses, or at least five doses of
the bacterial strains at different locations along the intestines,
at different times, and/or at different pH.
[0205] In some embodiments, the bacterial strains described herein
are in the form of live, vegetative cells. In some embodiments, the
bacterial strains described herein are in the form of spores. In
some embodiments, the bacterial strains described herewith are
lyophilized. As used herein, "lyophilization" or "freeze drying"
refers to the process of drying a material by first freezing it and
then encouraging the ice within it to sublimate in a vacuum
environment.
[0206] By way of non-limiting example, lyophilization can be via
methods known in the art, including those described in U.S. Pat.
No. 7,799,328, the contents of which are hereby incorporated by
reference in their entirety. In some embodiments, lyophilized
bacterial strains described herein are placed in an enterically
coated soft gel or capsule.
[0207] In one aspect, a pharmaceutical composition comprises a
lyophilized formulation further comprising a reducing agent. In
certain embodiments, the reducing agent comprises cysteine selected
from the group consisting of D-cysteine and L-cysteine. In another
aspect, cysteine is at a concentration of at least about 0.025%. In
one aspect, cysteine is at a concentration of about 0.025%. In
another aspect, cysteine is at a concentration of 0.025%. In
another aspect, another reducing agent other than cysteine is used
in lieu of, or in combination with cysteine. In an aspect, another
reducing agent is selected from the group comprising ascorbic acid,
sodium ascorbate, thioglycolic acid, sodium sulfite, sodium
bisulfite, sodium metabisulfite, potassium metabisulfite,
Glutathione, Methionine, thioglycerol, and alpha tocopherol.
[0208] In one aspect, cysteine is at a concentration of at least
about 0.005%, at least about 0.01%, at least about 0.015%, at least
about 0.02%, at least about 0.025%, at least about 0.03%, at least
about 0.035%, at least about 0.04%, at least about 0.045%, at least
about 0.05%, at least about 0.055%, at least about 0.06%, at least
about 0.065%, at least about 0.07%, at least about 0.075%, at least
about 0.08%, at least about 0.085%, at least about 0.09%, at least
about 0.095%, at least about 0.1%, at least about 0.12%, at least
about 0.14%, at least about 0.16%, at least about 0.18%, at least
about 0.2%, at least about 0.25%, at least about 0.3%, at least
about 0.4%, at least about 0.5%, at least about 0.6%, at least
about 0.7%, at least about 0.8%, at least about 0.9%, at least
about 1%, at least about 2%, at least about 4%, at least about 6%,
at least about 8%, at least about 10%, at least about 12%, at least
about 14%, at least about 16%, at least about 18%, at least about
20%, at least about 22%, at least about 24%, or at least about
26%.
[0209] In one aspect, a therapeutic composition comprises a
cryoprotectant. As used herein, a "cryoprotectant" refers to a
substance that is added to a formulation in order to protect an
active ingredient during freezing. In an aspect, a cryoprotectant
comprises, consists essentially of, or consists of polyethylene
glycol, skim milk, erythritol, arabitol, sorbitol, glucose,
fructose, alanine, glycine, proline, sucrose, lactose, ribose,
trehalose, dimethyl sulfoxide (DMSO), glycerol, or a combination
thereof. In an aspect of the present disclosure, a cryoprotectant
can be selected from the group comprising 5% Sucrose; 10% Sucrose;
10% Skim milk; 10% Trehalose with 2.5% sucrose; 5% Trehalose with
2.5% sucrose; 5% Mannitol; 5% Mannitol with 0.1% Polysorbate 80;
10% Mannitol; 10% Mannitol with 0.1% Polysorbate 80; 5% Trehalose;
5% Trehalose with 0.1% Polysorbate 80; 10% Trehalose; and 10%
Trehaolse with 0.1% Polysorbate 80.
[0210] In another aspect, a therapeutic composition comprises a
lyoprotectant. As used herein, a "lyoprotectant" refers to a
substance that is added to a formulation in order to protect an
active ingredient during the drying stage of a lyophilization (also
known as freeze-drying) process. In one aspect, the same substance
or the same substance combination is used as both a cryoprotectant
and a lyoprotectant. Exemplary lyoprotectants include sugars such
as sucrose or trehalose; an amino acid such as monosodium glutamate
or histidine; a methylamine such as betaine; a lyotropic salt such
as magnesium sulfate; a polyol such as trihydric or higher sugar
alcohols, e.g. glycerin, erythritol, glycerol, arabitol, xylitol,
sorbitol, and mannitol; propylene glycol; polyethylene glycol;
Pluronics; and combinations thereof. In one aspect, a lyoprotectant
is a non-reducing sugar, such as trehalose or sucrose. In one
aspect, a cryoprotectant or a lyoprotectant consists essentially
of, or consists of, one or more substances mentioned in this
paragraph and the paragraph above.
[0211] In one aspect, a cryoprotectant or a lyoprotectant comprise
an intracellular agent, e.g., DMSO, Glycerol, or PEG, which
penetrates inside the cell preventing the formation of ice crystals
that could result in membrane rupture. In another aspect, a
cryoprotectant or a lyoprotectant comprise an extracellular agent,
e.g., sucrose, trehalose, or dextrose, which does not penetrate
into the cell membrane but acts to improve the osmotic imbalance
that occurs during freezing.
[0212] In one aspect, the present disclosure provides a
pharmaceutical composition comprising a lyophilized fecal microbe
preparation comprising a lyophilization formulation comprising at
least about 12.5% trehalose.
[0213] In one aspect, a lyophilization formulation comprises at
least about 5%, at least about 7.5%, at least about 10%, at least
about 12.5%, at least about 13%, at least about 13.5%, at least
about 14%, at least about 14.5%, at least about 15%, at least about
15.5%, at least about 16%, at least about 16.5%, at least about
17%, at least about 17.5%, at least about 18%, at least about
18.5%, at least about 19%, at least about 19.5%, at least about
20%, at least about 22.5%, at least about 25%, at least about
27.5%, at least about 30%, at least about 32.5%, at least about
35%, at least about 37.5%, at least about 40%, at least about
42.5%, at least about 45%, at least about 47.5%, at least about
50%, at least about 52.5%, at least about 55%, at least about
57.5%, or at least about 60% of trehalose.
[0214] In various embodiments, the formulations of the present
invention take the form of those as described in one or more of
U.S. Pat. Nos. 8,535,713 and 8,9117,77 and US Patent Publication
Nos. 20120141585, 20120141531, 2006/001896, 2007/0292523,
2008/0020018, 2008/0113031, 2010/0203120, 2010/0255087,
2010/0297221, 2011/0052645, 2013/0243873, 2013/0330411,
2014/0017313, and 2014/0234418, the contents of which are hereby
incorporated by reference in their entirety.
[0215] In various embodiments, the formulations of the present
invention take the form of those as described in International
Patent Publication No. WO 2008/135090, the contents of which are
hereby incorporated by reference in their entirety.
[0216] In various embodiments, the formulations of the present
invention take the form of those described in one or more of U.S.
Pat. Nos. 4,196,564; 4,196,565; 4,247,006; 4,250,997; 4,268,265;
5,317,849; 6,572,892; 7,712,634; 8,074,835; 8,398,912; 8,440,224;
8,557,294; 8,646,591; 8,739,812; 8,810,259; 8,852,631; and
8,911,788 and US Patent Publication Nos. 2014/0302132;
2014/0227357; 20140088202; 20130287842; 2013/0295188; 2013/0307962;
and 20130184290, the contents of which are hereby incorporated by
reference in their entirety.
[0217] Administration and Dosage
[0218] It will be appreciated that the actual dose of the bacterial
strains (and/or additional therapeutic agents) to be administered
according to the present invention will vary according to, for
example, the particular dosage form and the mode of administration.
Many factors that may modify the action of the bacterial strains
(e.g., body weight, gender, diet, time of administration, route of
administration, rate of excretion, condition of the subject, drug
combinations, genetic disposition and reaction sensitivities) can
be taken into account by those skilled in the art. Administration
can be carried out continuously or in one or more discrete doses
within the maximum tolerated dose. Optimal administration rates for
a given set of conditions can be ascertained by those skilled in
the art using conventional dosage administration tests.
[0219] In various embodiments, the dose of the bacterial strains is
effective to modulate a patient's microbiome to favor an ecological
balance, i.e., treating or preventing a GI disorder described
herein.
[0220] In various embodiments, the dose of the bacterial strains
comprises at least 1.times.10.sup.4, 1.times.10.sup.5,
1.times.10.sup.6, 1.times.10.sup.7, 1.times.10.sup.8,
1.times.10.sup.9, 1.times.10.sup.10, 1.times.10.sup.11 or greater
than 1.times.10.sup.11 colony forming units (CFUs) or bacteria
(e.g., germinable bacterial spores).
[0221] Individual doses of the bacterial strains (and/or additional
therapeutic agents) can be administered in unit dosage forms (e.g.,
tablets or capsules) containing, for example, from about 0.01 mg to
about 5,000 mg, from about 0.01 mg to about 4,000 mg, from about
0.01 mg to about 3,000 mg, from about 0.01 mg to about 2,000 mg,
from about 0.01 mg to about 1,000 mg, from about 0.01 mg to about
950 mg, from about 0.01 mg to about 900 mg, from about 0.01 mg to
about 850 mg, from about 0.01 mg to about 800 mg, from about 0.01
mg to about 750 mg, from about 0.01 mg to about 700 mg, from about
0.01 mg to about 650 mg, from about 0.01 mg to about 600 mg, from
about 0.01 mg to about 550 mg, from about 0.01 mg to about 500 mg,
from about 0.01 mg to about 450 mg, from about 0.01 mg to about 400
mg, from about 0.01 mg to about 350 mg, from about 0.01 mg to about
300 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to
about 200 mg, from about 0.01 mg to about 150 mg, from about 0.01
mg to about 100 mg, from about 0.1 mg to about 90 mg, from about
0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg, from about
0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about
0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about
0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about
0.1 mg to about 5 mg, from about 0.1 mg to about 3 mg, from about
0.1 mg to about 1 mg of the active ingredient per unit dosage form,
or from about 5 mg to about 80 mg per unit dosage form. For
example, a unit dosage form can include about 0.01 mg, about 0.02
mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg,
about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about
0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg,
about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg,
about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8
mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350
mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about
600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg,
about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about
2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg of the
active ingredient, inclusive of all values and ranges
therebetween.
[0222] In one embodiment, the bacterial strains (and/or additional
therapeutic agents) is administered at an amount of from about 0.01
mg to about 100 mg daily, an amount of from about 0.01 mg to about
5,000 mg daily, about 0.01 mg to about 4,000 mg daily, about 0.01
mg to about 3,000 mg daily, about 0.01 mg to about 2,000 mg daily,
about 0.01 mg to about 1,000 mg daily, from about 0.01 mg to about
950 mg daily, from about 0.01 mg to about 900 mg daily, from about
0.01 mg to about 850 mg daily, from about 0.01 mg to about 800 mg
daily, from about 0.01 mg to about 750 mg daily, from about 0.01 mg
to about 700 mg daily, from about 0.01 mg to about 650 mg daily,
from about 0.01 mg to about 600 mg daily, from about 0.01 mg to
about 550 mg daily, from about 0.01 mg to about 500 mg daily, from
about 0.01 mg to about 450 mg daily, from about 0.01 mg to about
400 mg daily, from about 0.01 mg to about 350 mg daily, from about
0.01 mg to about 300 mg daily, from about 0.01 mg to about 250 mg
daily, from about 0.01 mg to about 200 mg daily, from about 0.01 mg
to about 150 mg daily, from about 0.1 mg to about 100 mg daily,
from about 0.1 mg to about 95 mg daily, from about 0.1 mg to about
90 mg daily, from about 0.1 mg to about 85 mg daily, from about 0.1
mg to about 80 mg daily, from about 0.1 mg to about 75 mg daily,
from about 0.1 mg to about 70 mg daily, from about 0.1 mg to about
65 mg daily, from about 0.1 mg to about 60 mg daily, from about 0.1
mg to about 55 mg daily, from about 0.1 mg to about 50 mg daily,
from about 0.1 mg to about 45 mg daily, from about 0.1 mg to about
40 mg daily, from about 0.1 mg to about 35 mg daily, from about 0.1
mg to about 30 mg daily, from about 0.1 mg to about 25 mg daily,
from about 0.1 mg to about 20 mg daily, from about 0.1 mg to about
15 mg daily, from about 0.1 mg to about 10 mg daily, from about 0.1
mg to about 5 mg daily, from about 0.1 mg to about 3 mg daily, from
about 0.1 mg to about 1 mg daily, or from about 5 mg to about 80 mg
daily. In various embodiments, the bacterial strains (and/or
additional therapeutic agents) is administered at a daily dose of
about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about
0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09
mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about
0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg,
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg,
about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250
mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg,
about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950
mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg,
or about 5,000 mg inclusive of all values and ranges
therebetween.
[0223] In some embodiments, a suitable dosage of the bacterial
strains (and/or additional therapeutic agents) is in a range of
about 0.01 mg/kg to about 100 mg/kg of body weight of the subject,
for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg,
about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07
mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about
0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about
0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about
1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about
1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about
1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg,
about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9
mg/kg, about 10 mg/kg body weight, about 20 mg/kg body weight,
about 30 mg/kg body weight, about 40 mg/kg body weight, about 50
mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body
weight, about 80 mg/kg body weight, about 90 mg/kg body weight, or
about 100 mg/kg body weight, inclusive of all values and ranges
therebetween. In other embodiments, a suitable dosage of the
bacterial strains (and/or additional therapeutic agents) in a range
of about 0.01 mg/kg to about 100 mg/kg of body weight, in a range
of about 0.01 mg/kg to about 90 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 80 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 70 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 60 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 50 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 40 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 30 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 20 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 10 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 9 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 8 mg/kg of body weight, in a range of
about 0.01 mg/kg to about 7 mg/kg of body weight, in a range of
0.01 mg/kg to about 6 mg/kg of body weight, in a range of about
0.05 mg/kg to about 5 mg/kg of body weight, in a range of about
0.05 mg/kg to about 4 mg/kg of body weight, in a range of about
0.05 mg/kg to about 3 mg/kg of body weight, in a range of about
0.05 mg/kg to about 2 mg/kg of body weight, in a range of about
0.05 mg/kg to about 1.5 mg/kg of body weight, or in a range of
about 0.05 mg/kg to about 1 mg/kg of body weight.
[0224] In an aspect, a therapeutic composition provided here
comprises a fecal microbiota comprising a Shannon Diversity Index
of greater than or equal to 0.3, greater than or equal to 0.4,
greater than or equal to 0.5, greater than or equal to 0.6, greater
than or equal to 0.7, greater than or equal to 0.8, greater than or
equal to 0.9, greater than or equal to 1.0, greater than or equal
to 1.1, greater than or equal to 1.2, greater than or equal to 1.3,
greater than or equal to 1.4, greater than or equal to 1.5, greater
than or equal to 1.6, greater than or equal to 1.7, greater than or
equal to 1.8, greater than or equal to 1.9, greater than or equal
to 2.0, greater than or equal to 2.1, greater than or equal to 2.2,
greater than or equal to 2.3, greater than or equal to 2.4, greater
than or equal to 2.5, greater than or equal to 3.0, greater than or
equal to 3.1, greater than or equal to 3.2, greater than or equal
to 3.3, greater than or equal to 3.4, greater than or equal to 3.5,
greater than or equal to 3.6, greater than or equal to 3.7, greater
than or equal to 3.8, greater than or equal to 3.9, greater than or
equal to 4.0, greater than or equal to 4.1, greater than or equal
to 4.2, greater than or equal to 4.3, greater than or equal to 4.4,
greater than or equal to 4.5, or greater than or equal to 5.0. In
another aspect, a therapeutic composition comprises fecal
microbiota comprising a Shannon Diversity Index of between 0.1 and
3.0, between 0.1 and 2.5, between 0.1 and 2.4, between 0.1 and 2.3,
between 0.1 and 2.2, between 0.1 and 2.1, between 0.1 and 2.0,
between 0.4 and 2.5, between 0.4 and 3.0, between 0.5 and 5.0,
between 0.7 and 5.0, between 0.9 and 5.0, between 1.1 and 5.0,
between 1.3 and 5.0, between 1.5 and 5.0, between 1.7 and 5.0,
between 1.9 and 5.0, between 2.1 and 5.0, between 2.3 and 5.0,
between 2.5 and 5.0, between 2.7 and 5.0, between 2.9 and 5.0,
between 3.1 and 5.0, between 3.3 and 5.0, between 3.5 and 5.0,
between 3.7 and 5.0, between 31.9 and 5.0, or between 4.1 and 5.0.
In one aspect, a Shannon Diversity Index is calculated at the
phylum level. In another aspect, a Shannon Diversity Index is
calculated at the family level. In one aspect, a Shannon Diversity
Index is calculated at the genus level. In another aspect, a
Shannon Diversity Index is calculated at the species level. In a
further aspect, a therapeutic composition comprises a preparation
of flora in proportional content that resembles a normal healthy
human fecal flora.
[0225] As used herein, "Shannon Diversity Index" refers to a
diversity index that accounts for abundance and evenness of species
present in a given community using the formula:
H = - i = 1 R ( p i ) ( ln ( p i ) ) ##EQU00001##
where H is Shannon Diversity Index, R is the total number of
species in the community, and pi is the proportion of R made up of
the ith species. Higher values indicate diverse and equally
distributed communities, and a value of 0 indicates only one
species is present in a given community. For further reference, see
Shannon and Weaver, (1949) The mathematical theory of
communication. The University of Illinois Press, Urbana. 117pp.
[0226] In accordance with certain embodiments of the invention, the
bacterial strains may be administered, for example, more than once
daily, about once per day, about every other day, about every third
day, about once a week, about once every two weeks, about once
every month, about once every two months, about once every three
months, about once every six months, or about once every year.
[0227] In one aspect, the present disclosure provides a method for
treating a disorder in a subject in need thereof, where the method
comprises administering to the subject a pharmaceutically active
dose of a therapeutic composition described herein. In one aspect,
the present disclosure provides a method for treating a disorder in
a subject in need thereof, where the method comprises administering
daily to the subject a pharmaceutically active dose of a
therapeutic composition described herein. In one aspect, a
therapeutic composition is administered to a patient in need
thereof at least once daily for at least two consecutive days. In
one aspect, a therapeutic composition is administered at least once
daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15
consecutive days. In another aspect, a therapeutic composition is
administered at least once daily for at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 consecutive weeks. In another aspect, a
therapeutic composition is administered at least twice, three
times, four times, or five times per week for at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In one aspect, a
therapeutic composition is administered at least once daily for at
most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
20 consecutive days or weeks. In another aspect, a therapeutic
composition is administered at least once daily for at most 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In
a further aspect, a therapeutic composition is administered at
least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
consecutive months or years, chronically for a subject's entire
life span, or an indefinite period of time.
[0228] In one aspect, a therapeutic composition is administered to
a patient in need thereof at least twice daily for at least two
consecutive days. In one aspect, a therapeutic composition is
administered at least twice daily for at least 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a
therapeutic composition is administered at least twice daily for at
least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks.
In one aspect, a therapeutic composition is administered at least
twice daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, or 20 consecutive days or week. In another aspect,
a therapeutic composition is administered at least twice daily for
at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks
or months. In a further aspect, a therapeutic composition is
administered at least twice for at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, or 12 consecutive months or years, chronically for a
subject's entire life span, or an indefinite period of time.
[0229] In one aspect, a therapeutic composition is administered to
a patient in need thereof at least three times daily for at least
two consecutive days. In one aspect, a therapeutic composition is
administered at least three times daily for at least 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another
aspect, a therapeutic composition is administered at least three
times daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
consecutive weeks. In one aspect, a therapeutic composition is
administered at least three times daily for at most 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days
or weeks. In another aspect, a therapeutic composition is
administered at least three times daily for at most 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In a further
aspect, a therapeutic composition is administered at least three
times for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
consecutive months or years, chronically for a subject's entire
life span, or an indefinite period of time.
[0230] In one aspect, the present disclosure provides a method for
treating a disorder in a subject in need thereof, where the method
comprises administering orally to the subject a pharmaceutically
active dose of a therapeutic composition comprising live,
non-pathogenic, synthetic bacterial mixture or live,
non-pathogenic, purified or extracted, fecal microbiota in a
lyophilized formulation described herein, where the dose is
administered at a dosing schedule of at least once or twice daily
for at least three consecutive days or weeks. In another aspect, a
dose is administered at least once, twice, or three times daily for
a period between 1 and 12 weeks, between 2 and 12 weeks, between 3
and 12 weeks, between 4 and 12 weeks, between 5 and 12 weeks,
between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12
weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1
and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between
4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks,
between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10
weeks, or between 10 and 11 weeks.
[0231] In one aspect, the present disclosure provides a method for
treating a disorder in a subject in need thereof by administering a
pharmaceutical composition described herein, where the method
comprises a first dosing schedule followed by a second dosing
schedule. In one aspect, a first dosing schedule comprises a
treatment or induction dose. In one aspect, a first dosing schedule
comprises a continuous dosing schedule. In another aspect, a second
dosing schedule comprises a maintenance dose lower than or equal to
a pharmaceutically active dose of a first dosing schedule. In
another aspect, a second dosing schedule lasts for at least about
2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 months. In one
aspect, a second dosing schedule lasts permanently, for a treated
subject's entire life span, or an indefinite period of time. In one
aspect, a second dosing schedule is a continuous dosing schedule.
In another aspect, a second dosing schedule is an intermittent
dosing schedule. In a further aspect, a second dosing schedule is
an intermittent dosing schedule comprising a treatment period of at
least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days
followed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, or 14 days. In another aspect, a second dosing
schedule comprises administering a second dose (e.g., a maintenance
dose) every other day, every two days, or every 3, 4, 5, 6, 7, 8
days. In another aspect, a maintenance dose is administered for an
extended period of time with or without titration (or otherwise
changing the dosage or dosing schedule). In one aspect, the
interval between a first and a second dosing schedule is at least
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In another
aspect, a second dosing schedule (e.g., a maintenance dose)
comprises a dosage about 2, 5, 10, 50, 100, 200, 400, 800, 1000,
5000 or more fold lower than the dosage used in a first dosing
schedule (e.g., an initial treatment dose). In another aspect, a
second dosing schedule (e.g., a maintenance dosing schedule) has an
equal or lower dosing frequency than a first dosing schedule (e.g.,
an initial treatment dosing schedule). In another aspect, a second
dosing schedule (e.g., a maintenance dosing schedule) has a higher
dosing interval than a first dosing schedule (e.g., an initial
treatment dosing schedule).
[0232] In one aspect, a first or second dosing schedule used in a
method can be once-a-week, twice-a-week, or thrice-a-week. The term
"once-a-week" means that a dose is administered once in a week,
preferably on the same day of each week. "Twice-a-week" means that
a dose is administered two times in a week, preferably on the same
two days of each weekly period. "Thrice-a-week" means that a dose
is administered three times in a week, preferably on the same three
days of each weekly period.
[0233] Additional Therapeutic Agents and Combination Therapy or
Co-Formulation
[0234] Administration of the present formulations may be combined
with additional therapeutic agents. Co-administration of the
additional therapeutic agent and the present formulations may be
simultaneous or sequential. Further; the present formulations may
comprise an additional therapeutic agent (e.g., via
co-formulation). For example, the additional therapeutic agent and
the bacterial strains may be combined into a single
formulation.
[0235] In one embodiment, the additional therapeutic agent and the
bacterial strains are administered to a subject simultaneously. The
term "simultaneously" as used herein, means that the additional
therapeutic agent and the bacterial strains are administered with a
time separation of no more than about 60 minutes, such as no more
than about 30 minutes, no more than about 20 minutes, no more than
about 10 minutes, no more than about 5 minutes, or no more than
about 1 minute. Administration of the additional therapeutic agent
and the bacterial strains can be by simultaneous administration of
a single formulation (e.g., a formulation comprising the additional
therapeutic agent and the bacterial strains) or of separate
formulations (e.g., a first formulation including the additional
therapeutic agent and a second formulation including the bacterial
strains).
[0236] Co-administration does not require the additional
therapeutic agents to be administered simultaneously, if the timing
of their administration is such that the pharmacological activities
of the additional therapeutic agent and the bacterial strains
overlap in time. For example, the additional therapeutic agent and
the bacterial strains can be administered sequentially. The term
"sequentially" as used herein means that the additional therapeutic
agent and the bacterial strains are administered with a time
separation of more than about 60 minutes. For example, the time
between the sequential administration of the additional therapeutic
agent and the bacterial strains can be more than about 60 minutes,
more than about 2 hours, more than about 5 hours, more than about
10 hours, more than about 1 day, more than about 2 days, more than
about 3 days, or more than about 1 week apart. The optimal
administration times will depend on the rates of metabolism,
excretion, and/or the pharmacodynamic activity of the additional
therapeutic agent and the bacterial strains being administered.
Either the additional therapeutic agent or the bacterial strains
may be administered first.
[0237] In a further embodiment, the additional therapeutic agent
and the bacterial strains are administered to a subject
simultaneously but the release of additional therapeutic agent and
the bacterial strains from their respective dosage forms (or single
unit dosage form if co-formulated) in the GI tract occurs
sequentially.
[0238] Co-administration also does not require the additional
therapeutic agents to be administered to the subject by the same
route of administration. Rather, each additional therapeutic agent
can be administered by any appropriate route, for example,
parentally or non-parentally.
[0239] In some embodiments, the additional therapeutic agent is an
agent used in the current standard-of-care induction therapies for
the pathogenic bacteria that the subject is currently infected with
and/or is at risk for being infected with, e.g., one or more
anti-inflammatory agents, probiotic agents, prebiotic agents,
antidiarrheal agents, analgesics, and antibiotic agents.
[0240] In some embodiments, the additional therapeutic agent is an
anti-inflammatory agent such as steroidal anti-inflammatory agents
or non-steroidal anti-inflammatory agents (NSAIDS). Steroids,
particularly the adrenal corticosteroids and their synthetic
analogues, are well known in the art. Examples of corticosteroids
useful in the present invention include, without limitation,
hydroxyltriamcinolone, alpha-methyl dexamethasone, beta-methyl
betamethasone, beclomethasone dipropionate, betamethasone benzoate,
betamethasone dipropionate, betamethasone valerate, clobetasol
valerate, desonide, desoxymethasone, dexamethasone, diflorasone
diacetate, diflucortolone valerate, fluadrenolone, fluclorolone
acetonide, flumethasone pivalate, fluosinolone acetonide,
fluocinonide, flucortine butylester, fluocortolone, fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and the balance of its esters, chloroprednisone,
clocortelone, clescinolone, dichlorisone, difluprednate,
flucloronide, flunisolide, fluoromethalone, fluperolone,
fluprednisolone, hydrocortisone, meprednisone, paramethasone,
prednisolone, prednisone, beclomethasone dipropionate. (NSAIDS)
that may be used in the present invention, include but are not
limited to, salicylic acid, acetyl salicylic acid, methyl
salicylate, glycol salicylate, salicylmides,
benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen,
ketoprofen, etofenamate, phenylbutazone, and indomethacin.
Additional anti-inflammatory agents are described, for example, in
U.S. Pat. No. 4,537,776, the entire contents of which are
incorporated by reference herein.
[0241] In some embodiments, the additional therapeutic agent is a
probiotic. Probiotics suitable for use in the present invention
include, but are not limited to, Saccharomyces boulardii;
Lactobacillus rhamnosus GG; Lactobacillus plantarum 299v;
Clostridium butyricum M588; Clostridium difficile VP20621
(non-toxigenic C. difficile strain); combination of Lactobacillus
casei, Lactobacillus acidophilus (Bio-K+CL1285); combination of
Lactobacillus casei, Lactobacillus bulgaricus, Streptococcus
thermophilus (Actimel); combination of Lactobacillus acidophilus,
Bifidobacterium bifidum (Florajen3); combination of Lactobacillus
acidophilus, Lactobacillus bulgaricus delbrueckii subsp.
bulgaricus, Lactobacillus bulgaricus casei, Lactobacillus
bulgaricus plantarum, Bifidobacterium longum, Bifidobacterium
infantis, Bifidobacterium breve, and Streptococcus salivarius
subsp. thermophilus (VSL #3)).
[0242] The compositions and methods of the present invention may
further comprise one or more prebiotics.
[0243] A prebiotic is a substrate that is selectively used by a
host microorganism to produce a health benefit in a
subject/patient. Without wishing to be bound by theory, prebiotics
are added to nutritionally supplement bacteria in the microbiome
and/or in a microbial composition, e.g., to stimulate the growth or
activity of one or more strains of beneficial bacteria.
Additionally, the prebiotics may be added to prevent "shock" to
bacterial strains subsequent to their isolation or purification,
freezing, freeze-drying, spray-drying, reconstitution in solution
and the like.
[0244] Examples of prebiotics include amino acids, ammonium
nitrate, amylose, barley mulch, biotin, carbonate, cellulose,
chitin, choline, fructooligosaccharides (FOSs), fructose,
galactooligosaccharides (GOSs), glucose, glycerol,
heteropolysaccharide, histidine, homopolysaccharide,
hydroxyapatite, inulin, isomaltulose, lactose, lactulose,
maltodextrins, maltose, mannooligosaccharides, tagatose, nitrogen,
oligodextrose, oligofructoses, oligofructose-enriched inulin,
oligosaccharides, pectin, phosphate salts, phosphorus,
polydextroses, polyols, potash, potassium, sodium nitrate, starch,
sucrose, sulfur, sun fiber, tagatose, thiamine,
trans-galactooligosaccharides, trehalose, vitamins, a water-soluble
carbohydrate, and/or xylooligosaccharides (XOSs).
[0245] In embodiments, a prebiotic can be added (e.g., in dry or
liquid forms) to a microbial composition of the present
invention.
[0246] Alternately, or additionally, a prebiotic can be included
(e.g., in dry or liquid forms) in a distinct pharmaceutical
composition which lacks a microbial composition of the present
invention.
[0247] A prebiotic may be provided to a subject before,
contemporaneously with, and/or after a pharmaceutical composition
comprising a microbial composition of the present invention is
administered, either in a pharmaceutical composition comprising the
microbial composition or in a pharmaceutical composition lacking a
microbial composition.
[0248] A prebiotic may be provided in a single dose or in multiple
doses. When provided as a single composition, the single
composition may comprise a single prebiotic or a mixture of
prebiotics. When provided in multiple compositions, each
composition may comprise a single prebiotic or a mixture of
prebiotics.
[0249] As examples, when multiple doses are provided, a first
composition comprising a prebiotic may include one specific
prebiotic, e.g., inulin, and a second composition may include a
second specific prebiotic, e.g., pectin. Alternately, a first
composition may include a mixture of prebiotics, e.g., inulin and
pectin and a second composition may include different mixture of
prebiotics, e.g., inulin and a FOS. A first composition may include
a mixture of prebiotics and a second composition may include one
specific prebiotic.
[0250] The amount of prebiotic provided to a subject/patient and/or
included in a composition depends on the specific prebiotic, the
specific bacterial strain of beneficial bacteria, and/or the
disease state of the subject/patient. In some embodiments, the
additional therapeutic agent is an antidiarrheal agent.
Antidiarrheal agents suitable for use in the present invention
include, but are not limited to, DPP-IV inhibitors, natural
opioids, such as tincture of opium, paregoric, and codeine,
synthetic opioids, such as diphenoxylate, difenoxin and loperamide,
bismuth subsalicylate, lanreotide, vapreotide and octreotide,
motiln antagonists, COX2 inhibitors like celecoxib, glutamine,
thalidomide and traditional antidiarrheal remedies, such as kaolin,
pectin, berberine and muscarinic agents.
[0251] In some embodiments, the additional therapeutic agent may be
an analgesic. Analgesics useful in the compositions and methods of
the present invention include, without limitation, morphine,
codeine, heroine, methadone and related compounds, thebaine,
orpiavine, and their derivatives, buprenorphine, the piperidines,
morphinans, benzomorphans, tetrahydroisoquinolines, thiambutanes,
benzylamines, tilidine, viminol, nefopam, capsaicin
(8-methyl-N-vanillyl-6E-nonenamide), "synthetic" capsaicin
(N-vanillylnonamide), and related compounds.
[0252] In some embodiments, the additional therapeutic agent is an
antibacterial agent, which includes, but is not limited to,
cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil,
cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin,
cefprozil, and ceftobiprole); fluoroquinolone antibiotics (cipro,
Levaquin, floxin, tequin, avelox, and norflox); tetracycline
antibiotics (tetracycline, minocycline, oxytetracycline, and
doxycycline); penicillin antibiotics (amoxicillin, ampicillin,
penicillin V, dicloxacillin, carbenicillin, vancomycin, and
methicillin); monobactam antibiotics (aztreonam); and carbapenem
antibiotics (ertapenem, doripenem, imipenem/cilastatin, and
meropenem). In some embodiments, the anti-bacterial agent may be
any of the penicillin, cephalosporin, monobactam, and carbapenem
antibiotics.
[0253] In some embodiments, the additional therapeutic agent
includes, but is not limited to, short-chain fatty acids, butyrate,
propionate, acetate, IL-2, IL-22, superoxide dismutase (SOD), GLP-2
and analogs, GLP-1, IL-10, IL-27, TGF-.beta.1, TGF-.beta.2,
N-acylphosphatidylethanolamines (NAPEs), elafin (also called
peptidase inhibitor 3 and SKALP), trefoil factor, melatonin,
tryptophan, PGD2, and kynurenic acid, indole metabolites, and other
tryptophan metabolites.
[0254] Aspects of the present invention relate to pharmaceutical
compositions comprising a bacterial mixture and an anti-cancer
therapeutic agent. The anti-cancer therapeutic agent may be a
chemotherapeutic agent. In a pharmaceutical composition of the
present invention, a chemotherapeutic agent that can be formulated
for oral administration and the bacterial mixture may be combined
and encapsulated together in a capsule. Alternately, the
chemotherapeutic agent may be included in a layer coating a capsule
which encapsulates the bacterial mixture. In embodiments, the
chemotherapeutic agent and the pharmaceutical composition
comprising the bacterial mixture are in separate dosage forms. In
embodiments, a subject in need thereof has received, is receiving,
or will receive chemotherapeutic agent, either with or separate
from a bacterial mixture.
[0255] In embodiments, any chemotherapeutic agent that can be
formulated for oral administration may be used in con. Examples of
such chemotherapeutic agents include Afinitor (everolimus),
Alecensa (alectinib), Alkeran (melphalan), Alunbrig (brigatinib),
Arimidex (anastrozole), Aromasin (exemestane), Bosulif (bosutinib),
Cabometyx (cabozantinib), Caprelsa (vandetanib), Casodex
(bicalutamide), Cometriq (cabozantinib), Cotellic (cobimetinib),
Cyclophosphamide (cyclophosphamide caps), Cytoxan
(Cyclophosphamide), Droxia (hydroxyurea), Emcyt (estramustine),
Erivedge (vismodegib), etoposide, Fareston (toremifene citrate),
Farydak (panobinostat), Femara (letrozole), flutamide, Gilotrif
(afatinib), Gleevec (imatinib), Gleostine (lomustine), Hexalen
(altretamine), Hycamtin (topotecan), Hydrea (hydroxyurea), Ibrance
(palbociclib), Iclusig (ponatinib), Idamycin (Idarubicin), Idhifa
(enasidenib), Imbruvica (ibrutinib), Inlyta (axitinib), Iressa
(gefitinib), Jakafi (ruxolitinib), Kisqali (ribociclib), Kisqali
Femara Co-Pack (ribociclib and letrozole), Lenvima (lenvatinib),
leucovorin, Leukeran (chlorambucil), Lonsurf
(trifluridine/tipiracil), Lynparza (olaparib), Lysodren (mitotane),
Matulane (procarbazine), Megace (megestrol acetate), Mekinist
(trametinib), mercaptopurine, Mesnex (mesna), methotrexate, Myleran
(busulfan), Navelbine (Vinorelbine), Nerlynx (neratinib), Nexavar
(sorafenib), Nilandron (nilutamide), Ninlaro (ixazomib), Odomzo
(sonidegib), Pomalyst (pomalidomide), Purixan (mercaptopurine
susp), Revlimid (lenalidomide), Rubraca (rucaparib), Rydapt
(midostaurin), Soltamox (tamoxifen citrate), Sprycel (dasatinib),
Stivarga (regorafenib), Sutent (sunitinib), Tabloid (thioguanine),
Tafinlar (dabrafenib), Tagrisso (osimertinib), tamoxifen, Tarceva
(erlotinib), Targretin (bexarotene), Tasigna (nilotinib), Temodar
(temozolomide), Thalomid (thalidomide), Toposar (Etoposide),
tretinoin, Trexall (methotrexate), Tykerb (lapatinib), Venclexta
(venetoclax), Votrient (pazopanib), Xalkori (crizotinib), Xatmep
(methotrexate soln), Xeloda (capecitabinea), Xtandi (enzalutamide),
Zejula (niraparib), Zelboraf (vemurafenib), Zolinza (vorinostat),
Zydelig (idelalisib), Zykadia (ceritinib), or Zytiga (abiraterone),
and a combination thereof.
[0256] In embodiments, a pharmaceutical composition can be in the
form of a capsule, tablet, or pill. In embodiments, the capsule,
tablet, or pill can be coated or otherwise compounded to provide a
dosage form affording the advantage of prolonged action. For
example, the capsule, tablet, or pill can comprise an inner dosage
(e.g., a bacterial mixture) and an outer dosage component (e.g., a
chemotherapeutic agent and/or additional therapeutic agent), the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass into the duodenum or colon and/or to be delayed
in release. A variety of materials can be used for such enteric
layers or coatings (as described herein). Exemplary materials
include a number of polymeric acids and mixtures of polymeric acids
with such materials as shellac, cetyl alcohol, and cellulose
acetate.
[0257] For all additional therapeutic agent compositions and
methods, targeting to various parts of the GI tract may be employed
as described herein.
[0258] In various embodiments, the patient of the present methods
is undergoing treatment with one or more additional therapeutic
agents and, by way of non-limitation, such additional therapeutic
agents may disrupt the microbiome.
[0259] Methods of Treatment
[0260] In various embodiments, the present invention provides
methods of modulating a patient's microbiome to provide or restore
an ecological balance. For instance, in various embodiments, herein
are provided methods for diminishing or inhibiting one or more
pathogenic bacteria as described elsewhere herein. In various
embodiments, the present mixtures of bacterial strains augment
growth of at least one type of bacteria not detectably present in a
patient's GI tract prior to administration and, in various
embodiments, which are non-pathogenic.
[0261] In various embodiments, the present invention provides
methods of restoring or enhancing ecological control over gut or
genitourinary pathogens or pathobionts in a patient.
[0262] In various embodiments, the present invention provides
methods of treating or preventing a disease or condition associated
with GI dysbiosis, comprising administering an effective amount of
a pharmaceutical composition described herein to a subject or a
patient need thereof.
[0263] In various embodiments, the present invention provides
methods of treating or preventing a disease or condition associated
with genitourinary dysbiosis, comprising administering an effective
amount of a pharmaceutical composition disclosed herein to a
subject or a patient need thereof.
[0264] Without wishing to be bound by theory, decolonization and
eradication of pathogenic bacteria relevant to the present
invention likely occurs through, one or more mechanisms. These
mechanisms are: (1) Direct inhibition of ARB growth through the
production of secreted soluble factors (see, below references 35 to
37 and 70 to 73); (2) Competition for the relevant niche/preferred
nutrients (see, below references 8, 38, 39, 74, and 75); (3) Immune
activation through host recognition of specific pathogen-associated
molecular patterns (PAMPs) (see, below references 40 and 41); and
(4) Production of Short Chain Fatty Acid (SCFA) by bacterial
strains which enhance the colonic barrier and can induce IgA
production (see, below references 40 and 41), and (5) activation of
Toll-Like Receptors (TLRs), which modulate the production of
antimicrobial peptides, which target many human bacterial
pathogens.
[0265] In the third and fifth mechanism, various bacterial products
stimulate the immune system through the TLR-MyD88 mediated pathway.
Stimulation of this pathway results in the upregulation of
antimicrobial proteins. Antimicrobial proteins and peptides (AMPs)
(e.g., the defensins or cathelicidins) are an important part of the
innate immune system and are expressed throughout the body. In the
gut, they are produced by the intestinal epithelial cells and
Paneth cells to defend against undesired bacterial species (both
commensal and pathogenic). AMP produced may be induced by a wide
variety of stimuli including but not limited to vitamin D,
cytokines, and microbial products. These stimulatory microbial
products can include but are not limited to lipopolysaccharide
(LPS), peptidoglycan, and flagellin. For example, flagellin is a
TLRS agonist that induces the production of the C-type lectin,
Reglllgamma. Reglllgamma has roles in killing Gram-positive
pathogens, including vancomycin resistant Enterococcus (VRE). There
is also evidence that anti-infective AMPs play a role in
attenuating host inflammatory responses through downregulation of
cytokine production. Induction of AMPs assists the host with a
properly modulated immune response to pathogens that accelerates
healing of the gut epithelia while eradicating the colonizing
pathogen.
[0266] In embodiments, the mixture of bacterial strains of the
present invention acts to protect patients through one or more
mechanisms: A first mechanism is direct inhibition of the
pathogenic bacteria through production of secreted products and a
second mechanism is through competition for nutrients in the
gut.
[0267] In various embodiments, the methods of the invention
comprise treating or preventing a microbiome-mediated disorder.
Illustrative microbiome-mediated disorder includes, but are not
limited to, for example, those found in Table 3 of WO 2014/121298,
the entire contents of which are incorporated herein by
reference.
[0268] In various embodiments, the present invention provides
methods of treating a patient suffering from a disease or condition
associated with GI dysbiosis. In some embodiments, the patient has
inflammatory bowel diseases (IBD), for example, Crohn's disease,
colitis (e.g., UC or microscopic colitis), or pouchitis. IBD is a
group of inflammatory conditions of the large intestine and, in
some cases, the small intestine. The main forms of IBD that may be
treated by the prevent invention include, but are not limited to,
Crohn's disease, UC, pouchitis, collagenous colitis, lymphocytic
colitis, ischemic colitis, diversion colitis, Behcet's syndrome,
infective colitis, and indeterminate colitis. In an embodiment, the
present invention provides methods of treating UC. In another
embodiment, the present invention provides methods of treating CD.
In a further embodiment, the present invention provides methods of
treating pouchitis.
[0269] In various embodiments, methods of the invention are
utilized for the treatment of UC. UC is one form of IBD. It is a
chronic disease of the colon, in which the lining of the colon
becomes inflamed and develops tiny open sores, or ulcers, that
produce pus and mucous. In some embodiments, methods of the
invention ameliorate, reduce, or eliminate the inflammation and/or
ulceration associated with UC. In some embodiments, methods of the
invention ameliorate, reduce, or eliminate one or more symptoms
associated with UC including but not limited to, abdominal
discomfort or pain, frequent emptying of the colon, lose and urgent
bowel movements, persistent diarrhea, bloody stool, loss of
appetite, and weight loss. In some embodiments, methods of the
invention may reduce or prevent the delay in growth and development
in children afflicted with UC.
[0270] In some embodiments, the present invention provides methods
of treating IBS. IBS is a common disorder that affects the colon
and can cause cramping, abdominal pain, bloating, gas, diarrhea and
constipation. IBS is classified based on the predominant symptom of
diarrhea (IBS with predominant diarrhea, IBS-D), constipation (IBS
with predominant constipation, IBS-C) or mixed symptoms (IBS with
alternating constipation and diarrhea, IBS-A). Methods of the
invention are effective in treating one or more of IBS-D, IBS-C,
and/or IBS-A. In some embodiments, methods of the invention
ameliorate, reduce, or eliminate one or more symptoms associated
with one or more of IBS-D, IBS-C, and/or IBS-A.
[0271] In some embodiments, the present invention provides for
compositions and methods for treating or preventing infections
(including colonization) by pathogenic bacteria and/or inhibiting
the growth or decrease the number of pathogenic bacteria in the GI
tract. In an embodiment, the pathogenic bacteria are enterobacteria
such as Salmonella. In various embodiments, the present invention
provides for compositions and methods that mitigate or prevent the
overgrowth of various coliforms in a patient's gut (including
coliforms that are virulent and/or antibiotic resistant).
Illustrative coliforms include Citrobacter, Enterobacer, Hafnia,
Kelbsiella, and Escherichia. In some embodiments, the methods and
compositions described herein prevent or diminish secondary
infections with resistant organisms.
[0272] In still other embodiments, the present invention provides
methods of treating a patient with an infectious disease of the
intestines, for example, CDI and/or a CDAD, nosocomial infection,
secondary emergent infection, amebiasis, intestinal tuberculosis,
or parasitic disorder. In some embodiments, the present invention
provides methods for treating or preventing a CDI and/or a CDAD,
comprising administering an effective amount of a composition
described herein to a subject or a patient need thereof. In various
embodiments, the CDI or CDAD comprises one or more of: C. difficile
diarrhea (CDD), C. difficile intestinal inflammatory disease,
colitis, pseudomembranous colitis, fever, abdominal pain,
dehydration and disturbances in electrolytes, megacolon,
peritonitis, and perforation and/or rupture of the colon.
[0273] In various embodiments, the disease or condition associated
with GI dysbiosis is treated or prevented in the context of initial
onset or relapse/recurrence (e.g., due to continued or restarted
antibiotic therapy). For example, in a patient that has previously
suffered from a GI dysbiosis, the present composition or
formulation may be administered upon the first symptoms of
recurrence in the patient. By way of non-limiting example, symptoms
of recurrence include, in a mild case, about 5 to about 10 watery
bowel movements per day, no significant fever, and only mild
abdominal cramps while blood tests may show a mild rise in the
white blood cell count up to about 15,000 (normal levels are up to
about 10,000), and, in a severe case, more than about 12 watery
stools per day, nausea, vomiting, high fever (e.g., about
102-104.degree. F.), rectal bleeding, severe abdominal pain (e.g.,
with tenderness), abdominal distention, and a high white blood
count (e.g., of about 15,000 to about 40,000).
[0274] In some embodiments, the methods of the present invention
are used to treat a subject or patient who is suffering from, or is
susceptible to, a disease or condition associated with GI
dysbiosis. For example, the patient may be undergoing or has
undergone an initial and/or adjunctive therapy that renders the
patient susceptible to a disease or condition associated with GI
dysbiosis. In some embodiments, the patient is undergoing
treatment, or has undergone treatment, with an antibiotic. For
example, the patient may have taken an antibiotic during the past
about 30 or so days and/or have an immune system that is weak
(e.g., from a chronic illness). In another example, the patient may
have recently been in the hospital, including in an intensive care
unit. Accordingly, in some embodiments, the methods and uses of the
present invention treat or prevent a nosocomial infection and/or a
secondary emergent infection and/or a hospital acquired infection
(HAI).
[0275] In various embodiments, the present invention provides
methods for treating antibiotic-induced adverse effects in the GI
tract, comprising administering an effective amount of a mixture of
bacterial strains described herein (and/or additional therapeutic
agents) to a subject in need thereof. In another embodiment, the
present invention provides methods for preventing an
antibiotic-induced adverse effect in the GI tract, comprising
administering an effective amount of a mixture of bacterial strains
described herein (and/or additional therapeutic agents) to a
subject in need thereof.
[0276] In various embodiments, the mixtures of bacterial strains as
described herein protect the intestinal microbiome from
antibiotics-induced damage. In some embodiments, the methods of the
invention treat or prevent an antibiotics-associated adverse effect
including but not limited to diarrhea, nausea, vomiting, dysgeusia,
colitis, and pseudomembranous colitis disease and/or symptoms. In
an embodiment, methods of the invention can be used to treat or
prevent antibiotic-associated diarrhea (MD).
[0277] Methods for measuring change and/or improvement in GI tract
function can include, but are not limited to: endoscopy for direct
examination of epithelium and mucosa; histological evaluation
and/or tissue procurement for direct evaluation of structural
changes and/or immune biomarkers; urine tests for assessment of
permeability with non-absorbable sugars and LPS levels; stool tests
for assessment of inflammation and/or microbiota changes (for
example by PCR); and/or blood tests for assessment of specific
markers, including CD4+ cell counts, Th17 cell counts, and/or LPS
levels.
[0278] In some embodiments, the methods of the present invention
treat or prevent a diarrheal disease including, but not limited to,
acute bloody diarrhea (e.g., dysentery), acute watery diarrhea
(e.g., cholera), checkpoint inhibitor-associated colitis, diarrhea
due to food poisoning, persistent diarrhea, and traveler's
diarrhea.
[0279] In various embodiments, the methods of the present invention
treat or prevent an IBD or related disease including, but not
limited to, Crohn's disease, ulcerative colitis, collagenous
colitis, lymphocytic colitis, diversion colitis, Behcet's disease,
intermediate colitis, short bowel syndrome, ulcerative proctitis,
proctosigmoiditis, left-sided colitis, pancolitis, and fulminant
colitis.
[0280] In various embodiments, the methods of the present invention
treat or prevent an autoimmune disorder including, but not limited
to, acute disseminated encephalomyelitis (ADEM), acute necrotizing
hemorrhagic leukoencephalitis, Addison's disease,
agammaglobulinemia, alopecia areata, amyloidosis, ankylosing
spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome
(APS), autoimmune angioedema, autoimmune aplastic anemia,
autoimmune dysautonomia, autoimmune hemolytic anemia, autoimmune
hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency,
autoimmune inner ear disease (AIED), autoimmune myocarditis,
autoimmune oophoritis, autoimmune pancreatitis, autoimmune
retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune
thyroid disease, autoimmune urticarial, axonal & neuronal
neuropathies, Balo disease, Behcet's disease, bullous pemphigoid,
cardiomyopathy, Castleman disease, celiac disease, Chagas disease,
chronic inflammatory demyelinating polyneuropathy (CIDP), chronic
recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome,
cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease,
Cogan's syndrome, cold agglutinin disease, congenital heart block,
Coxsackie myocarditis, CREST disease, essential mixed
cryoglobulinemia, demyelinating neuropathies, dermatitis
herpetiformis, dermatomyositis, Devic's disease (neuromyelitis
optica), discoid lupus, Dressler's syndrome, endometriosis,
eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum,
experimental allergic encephalomyelitis, Evans syndrome, fibrosing
alveolitis, giant cell arteritis (temporal arteritis), giant cell
myocarditis, glomerulonephritis, Goodpasture's syndrome,
granulomatosis with polyangiitis (GPA), Graves' disease,
Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's
thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes
gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic
purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,
immunoregulatory lipoproteins, inclusion body myositis,
interstitial cystitis, juvenile arthritis, juvenile idiopathic
arthritis, juvenile myositis, Kawasaki syndrome, Lambert-Eaton
syndrome, leukocytoclastic vasculitis, lichen planus, lichen
sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus
(systemic lupus erythematosus), chronic Lyme disease, Meniere's
disease, microscopic polyangiitis, mixed connective tissue disease
(MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple
sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis
optica (Devic's), neutropenia, ocular cicatricial pemphigoid, optic
neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcus),
paraneoplastic cerebellar degeneration, paroxysmal nocturnal
hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner
syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral
neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS
syndrome, polyarteritis nodosa, type I, II, & Ill autoimmune
polyglandular syndromes, polymyalgia rheumatic, polymyositis,
postmyocardial infarction syndrome, postpericardiotomy syndrome,
progesterone dermatitis, primary biliary cirrhosis, primary
sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic
pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia,
Raynaud's phenomenon, reactive arthritis, reflex sympathetic
dystrophy, Reiter's syndrome, relapsing polychondritis, restless
legs syndrome, retroperitoneal fibrosis, rheumatic fever,
rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,
scleroderma, Sjogren's syndrome, sperm & testicular
autoimmunity, stiff person syndrome, subacute bacterial
endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia,
Takayasu's arteritis, temporal arteritis/giant cell arteritis,
thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse
myelitis, type 1 diabetes, asthma, ulcerative colitis,
undifferentiated connective tissue disease (UCTD), uveitis,
vasculitis, vesiculobullous dermatosis, vitiligo, and Wegener's
granulomatosis.
[0281] In various embodiments, the methods of the present invention
treat or prevent or reduce a side effect associated with an
anti-cancer treatment. It is well known in the art that many
anti-cancer treatments can affect the gut biosis. For example,
chemotherapy can weaken the gut mucosa or change the
mucosal-associated microbiota, including reduced diversity in the
gut microbiome. Thus; such gut dysbiosis can lead to blood-stream
infections. Additionally, the anti-cancer therapy can promote
infection of and colonization of antibiotic resistant bacteria.
See, e.g., Papanicolas et al., "Not Just Antibiotics: Is Cancer
Chemotherapy Driving Antimicrobial Resistance?" Trends Microbiol.
2018 May; 26(5):393-400. Accordingly, bacterial mixtures of the
present invention are useful in cancer-related applications, at
least in decreasing the severity of a side effect and up to
eliminating the side effect, e.g., in part, by promoting the
decolonization and/or eradicating various pathogenic bacteria
and/or repairing/repopulating his/her gut microbiome after
receiving the anti-cancer therapeutic agent and/or anti-cancer
therapy.
[0282] Moreover, the bacterial mixtures of the present invention
are useful in cancer-related applications by increasing efficacy of
an anti-cancer therapeutic agent and/or anti-cancer therapy by, at
least, promoting the beneficial and desired effects of an
anti-cancer therapeutic agent and/or anti-cancer therapy, i.e.,
killing cancer cells, reducing tumor size, and/or simulating an
immune response against a cancer cell or tumor.
[0283] In aspects and embodiments, and without wishing to be bound
by theory, the bacterial mixtures of the present invention may
exert beneficial effects in oncology by maintaining responsiveness
of a tumor, allowing an increased treatment dose (of the
anti-cancer therapy) than otherwise possible, permitting
administration of more frequent treatment doses (e.g., patient
would not have to miss a session due to side effects), and/or
boosting the immune system (e.g., for checkpoint inhibitor
therapy).
[0284] In various embodiments, a subject in need thereof has
received, is receiving, or will receive an anti-cancer therapeutic
agent and/or an anti-cancer therapy.
[0285] Aspects of the present invention relate to methods for
preventing or treating a cancer comprising administering a
pharmaceutical composition comprising a microbial composition (with
or without a chemotherapeutic agent that can be formulated for oral
administration, as described herein) and administering an
anti-cancer therapy.
[0286] In embodiments, a pharmaceutical composition is administered
simultaneously (as described herein) with the anti-cancer
therapy.
[0287] Alternately, the pharmaceutical composition and the
anti-cancer therapy are administered sequentially. The term
"sequentially" as used herein means that the anti-cancer therapy
and the pharmaceutical composition are administered with a time
separation of more than about 60 minutes. For example, the time
between the sequential administration of the anti-cancer therapy
and the pharmaceutical composition can be more than about 60
minutes, more than about 2 hours, more than about 5 hours, more
than about 10 hours, more than about 1 day, more than about 2 days,
more than about 3 days, more than about 1 week apart, more than 1
month apart, or longer. The optimal administration time will depend
on the specific anti-cancer therapy and the pharmaceutical
composition being administered. Either the anti-cancer therapy or
the pharmaceutical composition may be administered first. In
embodiments, the subject is administered pharmaceutical composition
prior to the anti-cancer therapy, thereby helping ensure that the
subject has a healthy gut biome prior to receiving the anti-cancer
therapy. Alternately, the subject is administered pharmaceutical
composition after the anti-cancer therapy, thereby helping the
subject repair/repopulate his/her gut biome after receiving the
anti-cancer therapy.
[0288] In embodiments, a bacterial mixture is administered
enterally, e.g., orally, and the anti-cancer therapy is a
chemotherapy or a targeted therapy which is administered
parentally.
[0289] In aspects and embodiments, the anti-cancer therapy is a
radiation therapy.
[0290] In aspects and embodiments, the anti-cancer therapy is a
surgery, i.e., to excise a tumor or an organ/tissue comprising
cancerous cells.
[0291] In aspects and embodiments, the anti-cancer therapy
comprises a chemotherapy. Examples of chemotherapeutic agents
include 5-FU (Fluorouracil), Abemaciclib, Abiraterone Acetate,
Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized
Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, Acalabrutinib,
AC-T, ADE, Adriamycin (Doxorubicin), Afatinib Dimaleate, Afinitor
(Everolimus), Afinitor Difsperz (Everolimus), Akynzeo (Netupitant
and Palonosetron), Aldara (Imiquimod), Aldesleukin, Alecensa
(Alectinib), Alectinib, Alimta (PEMETREXED), Aliqopa (Copanlisib
Hydrochloride), Alkeran (Melphalan), Aloxi (Palonosetron
Hydrochloride), Alunbrig (Brigatinib), Ambochlorin (Chlorambucil),
Amboclorin (Chlorambucil), Amifostine, Aminolevulinic Acid,
Anastrozole, Aprepitant, Aredia (Pamidronate), Arimidex
(Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic
Trioxide, Asparaginase Erwinia chrysanthemi, Axicabtagene
Ciloleucel, Axitinib, Azacitidine, BEACOPP, Becenum (Carmustine),
Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP,
Bexarotene, Bicalutamide, BiCNU (Carmustine), Blenoxane
(Bleomycin), Bortezomib, Bosulif (Bosutinib), Bosutinib,
Brigatinib, BuMel, Busulfan, Busulfex (Busulfan)C, Cabazitaxel,
Cabometyx (Cabozantinib), Cabozantinib-S-Malate, CAF, Calquence
(Acalabrutinib), Camptosar (Irinotecan Hydrochloride),
Capecitabine, CAPDX, Caprelsa (Vandetanib), Carac
(Fluorouracil--Topical), Carboplatin, CARBOPLATIN-TAXOL,
Carfilzomib, Carmubris (Carmustine), Carmustine, Casodex
(Bicalutamide), CeeNU (Lomustine), CEM, Ceritinib, Cerubidine
(Daunorubicin), Cervarix (Recombinant HPV Bivalent Vaccine), CEV,
Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Cladribine,
Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine),
Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib),
Copanlisib Hydrochloride, COPDAC, COPP, COPP-ABV, Cosmegen
(Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP,
Cyclophosphamide, Cyfos (Ifosfamide), Cytarabine, Cytarabine
Liposome, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide),
Cytoxan (Cytoxan), Dabrafenib, Dacarbazine, Dacogen (Decitabine),
Dactinomycin, Dasatinib, Daunorubicin Hydrochloride, Daunorubicin
Hydrochloride and Cytarabine Liposome, DaunoXome (Daunorubicin
Lipid Complex), Decadron (Dexamethasone), Decitabine, Defibrotide
Sodium, Defitelio (Defibrotide Sodium), Degarelix, Denileukin
Diftitox, DepoCyt (Cytarabine Liposome), Dexamethasone,
Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak
(Dexamethasone), Dexrazoxane Hydrochloride, Docefrez (Docetaxel),
Docetaxel, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin
Hydrochloride, Doxorubicin Hydrochloride Liposome, Dox-SL
(Doxorubicin Hydrochloride Liposome), Droxia (Hydroxyurea), DTIC
(Decarbazine), DTIC-Dome (Dacarbazine), Efudex
(Fluorouracil--Topical), Eligard (Leuprolide), Elitek
(Rasburicase), Ellence (Ellence (epirubicin)), Eloxatin
(Oxaliplatin), Elspar (Asparaginase), Eltrombopag Olamine, Emcyt
(Estramustine), Emend (Aprepitant), Enasidenib Mesylate,
Enzalutamide, Epirubicin Hydrochloride, EPOCH, Eribulin Mesylate,
Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze
(Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos
(Etoposide Phosphate), Etoposide, Etoposide Phosphate, Eulexin
(Flutamide), Evacet (Doxorubicin Hydrochloride Liposome),
Everolimus, Evista (Raloxifene Hydrochloride), Evomela (Melphalan
Hydrochloride), Exemestane, Fareston (Toremifene), Farydak
(Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole),
Filgrastim, Firmagon (Degarelix), FloPred (Prednisolone), Fludara
(Fludarabine), Fludarabine Phosphate, Fluoroplex (Fluorouracil),
Fluorouracil, Flutamide, Folex (Methotrexate), Folex PFS
(Methotrexate), FOLFIRI, FOLFIRINOX, FOLFOX, Folotyn
(Pralatrexate), FUDR (FUDR (floxuridine)), FU-LV, Fulvestrant,
Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9
(Recombinant HPV Nonavalent Vaccine), Gefitinib, Gemcitabine
Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE-OMLIPLATIN,
Gemzar (Gemcitabine), Gilotrif (Afatinib Dimaleate), Gilotrif
(Afatinib), Gleevec (Imatinib Mesylate), Gliadel (Carmustine),
Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate),
Hemangeol (Propranolol Hydrochloride), Hexalen (Altretamine), HPV
Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant,
HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan
Hydrochloride), Hycamtin (Topotecan), Hydrea (Hydroxyurea),
Hydroxyurea, Hyper-CVAD, Ibrance (Palbociclib), Ibrutinib, ICE,
Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Idarubicin
Hydrochloride, Idelalisib, Idhifa (Enasidenib), Ifex (Ifosfamide),
Ifosfamide, Ifosfamidum (Ifosfamide), Imatinib Mesylate, Imbruvica
(Ibrutinib), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta
(Axitinib), Iressa (Gefitinib), Irinotecan Hydrochloride,
Irinotecan Hydrochloride Liposome, Istodax (Romidepsin),
Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi
(Ruxolitinib Phosphate), Jakafi (Ruxolitinib), JEB, Jevtana
(Cabazitaxel), Keoxifene (Raloxifene Hydrochloride), Kepivance
(Palifermin), Kisqali (Ribociclib), Kyprolis (Carfilzomib),
Lanreotide Acetate, Lanvima (Lenvatinib), Lapatinib Ditosylate,
Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),
Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leukine
(Sargramostim), Leuprolide Acetate, Leustatin (Cladribine), Levulan
(Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox
(Doxorubicin Hydrochloride Liposome), Lomustine, Lonsurf
(Trifluridine and Tipiracil), Lupron (Leuprolide), Lynparza
(Olaparib), Lysodren (Mitotane), Marqibo (Vincristine Sulfate
Liposome), Marqibo Kit (Vincristine Lipid Complex), Matulane
(Procarbazine), Mechlorethamine Hydrochloride, Megace (Megestrol),
Megestrol Acetate, Mekinist (Trametinib), Melphalan, Melphalan
Hydrochloride, Mercaptopurine, Mesnex (Mesna), Metastron
(Strontium-89 Chloride), Methazolastone (Temozolomide),
Methotrexate, Methotrexate LPF (Methotrexate), Methylnaltrexone
Bromide, Mexate (Methotrexate), Mexate-AQ (Methotrexate),
Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex
(Mitomycin C), MOPP, Mostarina (Prednimustine), Mozobil
(Plerixafor), Mustargen (Mechlorethamine), Mutamycin (Mitomycin),
Myleran (Busulfan), Mylosar (Azacitidine), Nanoparticle Paclitaxel
(Paclitaxel Albumin-stabilized Nanoparticle Formulation), Navelbine
(Vinorelbine), Nelarabine, Neosar (Cyclophosphamide), Neratinib
Maleate, Nerlynx (Neratinib), Netupitant and Palonosetron
Hydrochloride, Neulasta (filgrastim), Neulasta (pegfilgrastim),
Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilutamide),
Nilotinib, Nilutamide, Ninlaro (Ixazomib), Nipent (Pentostatin),
Niraparib Tosylate Monohydrate, Nolvadex (Tamoxifen), Novantrone
(Mitoxantrone), N plate (Romiplostim), Odomzo (Sonidegib), OEPA,
OFF, Olaparib, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase),
Oncovin (Vincristine), Ondansetron Hydrochloride, Onivyde
(Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox),
Onxol (Paclitaxel), OPPA, Orapred (Prednisolone), Osimertinib,
Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle
Formulation, PAD, Palbociclib, Palifermin, Palonosetron
Hydrochloride, Palonosetron Hydrochloride and Netupitant,
Pamidronate Disodium, Panobinostat, Panretin (Alitretinoin),
Paraplat (Carboplatin), Pazopanib Hydrochloride, PCV, PEB,
Pediapred (Prednisolone), Pegaspargase, Pegfilgrastim, Pemetrexed
Disodium, Platinol (Cisplatin), PlatinolAQ (Cisplatin), Plerixafor,
Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Pralatrexate,
Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin),
Promacta (Eltrombopag Olamine), Propranolol Hydrochloride,
Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium 223
Dichloride, Raloxifene Hydrochloride, Rasburicase, R--CHOP, R--CVP,
Reclast (Zoledronic acid), Recombinant Human Papillomavirus (HPV)
Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonavalent
Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent
Vaccine, Regorafenib, Relistor (Methylnaltrexone Bromide), R-EPOCH,
Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Ribociclib,
R-ICE, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubex
(Doxorubicin), Rubidomycin (Daunorubicin Hydrochloride), Rubraca
(Rucaparib), Rucaparib Camsylate, Ruxolitinib Phosphate, Rydapt
(Midostaurin), Sandostatin (Octreotide), Sandostatin LAR Depot
(Octreotide), Sclerosol Intrapleural Aerosol (Talc), Soltamox
(Tamoxifen), Somatuline Depot (Lanreotide Acetate), Sonidegib,
Sorafenib Tosylate, Sprycel (Dasatinib), STANFORD V, Sterapred
(Prednisone), Sterapred DS (Prednisone), Sterile Talc Powder
(Talc), Steritalc (Talc), Sterecyst (Prednimustine), Stivarga
(Regorafenib), Sunitinib Malate, Supprelin LA (Histrelin), Sutent
(Sunitinib Malate), Sutent (Sunitinib), Synribo (Omacetaxine
Mepesuccinate), Tabloid (Thioguanine), TAC, Tafinlar (Dabrafenib),
Tagrisso (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen
Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib), Targretin
(Bexarotene), Tasigna (Decarbazine), Tasigna (Nilotinib), Taxol
(Paclitaxel), Taxotere (Docetaxel), Temodar (Temozolomide),
Temozolomide, Temsirolimus, Tepadina (Thiotepa), Thalidomide,
Thalomid (Thalidomide), TheraCys BCG (BCG), Thioguanine, Thioplex
(Thiotepa), Thiotepa, TICE BCG (BCG), Tisagenlecleucel, Tolak
(Fluorouracil--Topical), Toposar (Etoposide), Topotecan
Hydrochloride, Toremifene, Torisel (Temsirolimus), Totect
(Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib, Treanda
(Bendamustine hydrochloride), Trelstar (Triptorelin), Trexall
(Methotrexate), Trifluridine and Tipiracil Hydrochloride, Trisenox
(Arsenic trioxide), Tykerb (lapatinib), Uridine Triacetate, VAC,
Valrubicin, Valstar (Valrubicin Intravesical), Valstar
(Valrubicin), VAMP, Vandetanib, Vantas (Histrelin), Varubi
(Rolapitant), VeIP, Velban (Vinblastine), Velcade (Bortezomib),
Velsar (Vinblastine Sulfate), Vemurafenib, Venclexta (Venetoclax),
Vepesid (Etoposide), Verzenio (Abemaciclib), Vesanoid (Tretinoin),
Viadur (Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine
Sulfate, Vincasar PFS (Vincristine), Vincrex (Vincristine),
Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine
Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze
(Glucarpidase), Vorinostat, Votrient (Pazopanib), Vumon
(Teniposide), Vyxeos (Daunorubicin Hydrochloride and Cytarabine
Liposome), W, Wellcovorin (Leucovorin Calcium), Wellcovorin IV
(Leucovorin), Xalkori (Crizotinib), XELIRI, Xeloda (Capecitabine),
XELOX, Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide),
Yescarta (Axicabtagene Ciloleucel), Yondelis (Trabectedin), Zaltrap
(Ziv-Aflibercept), Zanosar (Streptozocin), Zarxio (Filgrastim),
Zejula (Niraparib), Zelboraf (Vemurafenib), Zinecard (Dexrazoxane
Hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron
Hydrochloride), Zoladex (Goserelin), Zoledronic Acid, Zolinza
(Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus),
Zydelig (Idelalisib), Zykadia (Ceritinib), Zytiga (Abiraterone
Acetate), and Zytiga (Abiraterone).
[0292] In embodiments, the chemotherapy is a hormonal therapy.
Illustrative hormone therapeutics include aromatase inhibitors,
e.g., Letrozole, anastrozole, exemestane, aminoglutethimide;
gonadotropin-releasing hormone (GnRH) analogues, e.g., leuprorelin
and goserelin; hormone receptor antagonists, e.g., selective
estrogen receptor modulators (as examples, tamoxifen, raloxifene,
toremifene and fulvestrant) and antiandrogens, e.g., flutamide and
bicalutamide; and hormone supplementation, e.g., megestrol acetate,
medroxyprogesterone acetate, fluoxymesterone, diethylstilbestrol,
estrace, polyestradiol phosphate, and octreotide.
[0293] In aspects and embodiments, the anti-cancer therapy is an
immuno-oncology therapy. An immuno-oncology therapy comprises at
least one molecule capable of binding and/or recognizing a
tumor-cell antigen and/or a cancer-cell antigen. Examples,
tumor-cell antigens and/or a cancer-cell antigens include but are
not limited to, carbonic anhydrase IX (CAIX), 5T4, CD19, CD20,
CD22, CD30, CD33, CD38, CD47, CS1, CD138, Lewis-Y, L1-CAM, MUC16,
ROR-1, IL13R.alpha.2, gp100, prostate stem cell antigen (PSCA),
prostate-specific membrane antigen (PSMA), B-cell maturation
antigen (BCMA), human papillomavirus type 16 E6 (HPV-16 E6), CD171,
folate receptor alpha (FR-.alpha.), GD2, human epidermal growth
factor receptor 2 (HER2), mesothelin, EGFRvlll, fibroblast
activation protein (FAP), carcinoembryonic antigen (CEA), and
vascular endothelial growth factor receptor 2 (VEGF-R2), as well as
other tumor antigens well known in the art. Additional illustrative
tumor antigens include, but are not limited to MART-1/Melan-A,
gp100, Dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding
protein (ADAbp), cyclophilin b, Colorectal associated antigen
(CRC)-0017-1A/GA733, Carcinoembryonic Antigen (CEA) and its
immunogenic epitopes CAP-1 and CAP-2, etv6, aml1, Prostate Specific
Antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3,
T-cell receptor/CD3-zeta chain, MAGE-family of tumor antigens
(e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6,
MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, MAGE-Xp2
(MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1,
MAGE-C2, MAGE-C3, MAGE-C4, MAGE-05), GAGE-family of tumor antigens
(e.g., GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7,
GAGE-8, GAGE-9), BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4,
tyrosinase, p53, MUC family, HER2/neu, p21ras, RCAS1,
.alpha.-fetoprotein, E-cadherin, .alpha.-catenin, .beta.-catenin
and .gamma.-catenin, p120ctn, gp100 Pmel117, PRAME, NY-ESO-1,
cdc27, adenomatous polyposis coli protein (APC), fodrin, Connexin
37, Ig-idiotype, p15, gp75, GM2 and GD2 gangliosides, viral
products such as human papilloma virus proteins, Smad family of
tumor antigens, Imp-1, NA, EBV-encoded nuclear antigen (EBNA)-1,
brain glycogen phosphorylase, SSX-1, SSX-2 (HOM-MEL-40), SSX-1,
SSX-4, SSX-5, SCP-1 CT-7, c-erbB-2, CD19, CD37, CD56, CD70, CD74,
CD138, AGS16, MUC1, GPNMB, Ep-CAM, PD-L1, and PD-L2.
[0294] In embodiments, the tumor-cell antigen and/or a cancer-cell
antigen is a checkpoint molecule. The checkpoint molecule may be a
stimulatory checkpoint molecule, e.g., CD27, CD28, CD40, CD122,
CD137, OX40, GITR, and ICOS. The checkpoint molecule may be an
inhibitory checkpoint molecule, e.g., 2B4, A2AR, B-7 family ligands
(including, but are not limited to, B7-1, B7-2, B7-DC, B7-H1,
B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7), BTLA, CD115,
CD160/By55, CD172a/SIRP.alpha., CD200, CD223, CD244, CEACAM, CHK 1
and CHK2 kinases, CTLA-4, GAL9, HVEM, IDO, KIR, LAG3, PD-1, PD-L1,
PD-L2, TIGIT, TIM-3, TMIGD2, and VISTANSIG8.
[0295] In embodiments, the immuno-oncology therapy is
protein-based, e.g., antibody, fusion protein, and/or cytokine.
[0296] In embodiments, the antibody is Adcetris (Brentuximab
Vedotin), Ado-Trastuzumab Emtansine, Alemtuzumab, Arzerra
(Ofatumumab), Atezolizumab, Avastin (Bevacizumab), Avelumab,
Bavencio (Avelumab), Besponsa (Inotuzumab Ozogamicin), Bevacizumab,
Bexxar (Tositumomab), Blinatumomab, Blincyto (Blinatumomab), BMS
936559, Brentuximab Vedotin, Campath (Alemtuzumab), Cetuximab,
Cinqair (Reslizumab), Cyramza (Ramucirumab), Daratumumab, Darzalex
(Daratumumab), Denosumab, Dinutuximab, Durvalumab, Elotuzumab,
Empliciti (Elotuzumab), Erbitux (Cetuximab), Folfiri-Bevacizumab,
Folfiri-Cetuximab, Gazyva (Obinutuzumab), Gemtuzumab Ozogamicin,
Herceptin (Trastuzumab), Ibritumomab Tiuxetan, lmfinzi
(Durvalumab), Inotuzumab Ozogamicin, Ipilimumab, Kadcyla
(Ado-trastuzumab Emtansine), Keytruda (Pembrolizumab), Lartruvo
(Olaratumab), MK-3475, MPDL328OA, Mylotarg (Gemtuzumab Ozogamicin),
Necitumumab, Nivolumab, Obinutuzumab, Ofatumumab, Olaratumab,
Opdivo (Nivolumab), Panitumumab, Perjeta (Pertuzumab), Pertuzumab,
Pembrolizumab, Pidilizumab, Portrazza (Necitumumab), Prolia
(Denosumab), Ramucirumab, Rituxan (Rituximab), Rituximab and
Hyaluronidase Human, Siltuximab, Sylvant (Siltuximab), Tecentriq
(Atezolizumab), Trastuzumab, Unituxin (Dinutuximab), Vectibix
(Panitumumab), Xgeva (Denosumab), Yervoy (Ipilimumab), and Zevalin
(Ibritumomab Tiuxetan).
[0297] In embodiments, the immuno-oncology therapy includes an
engineered protein or a fusion protein. In embodiments, the
engineered protein or fusion protein binds to one or more
tumor-cell antigens and/or cancer-cell antigens. In embodiments,
the fusion protein binds to one or more tumor-cell antigens and/or
cancer-cell antigens and is conjugated to a chemotherapeutic agent
(as described herein).
[0298] In embodiments, the immuno-oncology therapy includes a
cytokine, e.g., which binds to one or more tumor-cell antigens
and/or cancer-cell antigens. In embodiments, the cytokine is
Interferon Alfa-2b, Interleukin-2 (Aldesleukin), Intron A alfab
(Interferon alfa-2a), Peginterferon Alfa-2b, PEG-Intron
(Peginterferon Alfa-2b), Recombinant Interferon Alfa-2b, RoferonA
alfaa (Interferon alfa-2a), and Sylatron (Peginterferon
Alfa-2b).
[0299] In embodiments, binding and/or recognizing a tumor-cell
antigen and/or a cancer-cell antigen blocks and/or prevents
downstream signaling of the tumor-cell antigen and/or cancer-cell
antigen. Alternately, binding and/or recognizing a tumor-cell
antigen and/or a cancer-cell antigen activates and/or stimulates
downstream signaling of the tumor-cell antigen and/or cancer-cell
antigen.
[0300] In embodiments, the immuno-oncology therapy is a cell-based
immuno-oncology therapy, e.g., relating to adoptive cell transfer
(ACT). The ACT may be autologous or allogenic.
[0301] In embodiments, the cell-based immuno-oncology therapy
comprises use of Chimeric Antigen Receptor (CAR) T-cell. Exemplary
CAR T-cell therapy include, but are not limited to, JCAR014 (Juno
Therapeutics), JCAR015 (Juno Therapeutics), JCAR017 (Juno
Therapeutics), JCAR018 (Juno Therapeutics), JCAR020 (Juno
Therapeutics), JCAR023 (Juno Therapeutics), JCAR024 (Juno
Therapeutics), CTL019 (Novartis), Kymriah (or tisagenlecleucel;
Novartis), KTE-C19 (Kite Pharma), BPX-401 (Bellicum
Pharmaceuticals), BPX-501 (Bellicum Pharmaceuticals), BPX-601
(Bellicum Pharmaceuticals), bb2121 (Bluebird Bio), CD-19 Sleeping
Beauty cells (Ziopharm Oncology), UCART19 (Cellectis), UCART123
(Cellectis), UCART38 (Cellectis), UCARTCS1 (Cellectis), OXB-302
(Oxford BioMedica, MB-101 (Mustang Bio), and CAR T-cells developed
by Innovative Cellular Therapeutics.
[0302] In embodiments, the cell-based immuno-oncology therapy
comprises use of an antigen-presenting cell (APC). In embodiments,
the APC-related therapy comprises use of dendritic cells or other
APCs that express tumor-cell antigens or cancer-cell antigens (as
described herein). In one example, the APC is Sipuleucel-T
(APC8015, trade name Provenge; Dendreon Corporation).
[0303] In embodiments, the cell-based immuno-oncology therapy
comprises use of engineered T Cell Receptors (TCR) which recognize
tumor-cell antigens or cancer-cell antigens (as described
herein).
[0304] In embodiments, the cell-based immuno-oncology therapy
comprises use of tumor infiltrating lymphocytes (TIL), e.g.,
adoptive transfer of TILs, which recognize tumor-cell antigens or
cancer-cell antigens (as described herein).
[0305] In various embodiments, the mixtures of bacterial strains
may stimulate and/or activate Toll-like receptor activity (e.g.,
TLR1, and/or TLR2, and/or TLR3, and/or TLR4, and/or TLR5, and/or
TLR6, and/or TLR7, and/or TLR8, and/or TLR9, and/or TLR10, and/or
TLR11, and/or TLR12, and/or TLR13).
[0306] In various embodiments, the methods of the present invention
treat or prevent various bloodstream infections (BSI), catheter or
intravascular-line infections (e.g., central-line infections),
chronic inflammatory diseases, meningitis, pneumonia, e.g.,
ventilator-associated pneumonia, skin and soft tissue infections,
surgical-site infections, urinary tract infections (e.g.,
antibiotic-resistant urinary tract infections and
catheter-associated urinary tract infections), wound infections,
and/or other well-known infections: antibiotic-resistant infections
and antibiotic-sensitive infections.
[0307] In various embodiments, the methods of the present invention
treat or prevent various GI disorders disclosed herein and/or as
known in the art to be a result of gut dysbiosis.
[0308] In various embodiments, the methods of the present invention
reduce GI immunoactivation and inflammation.
[0309] In various embodiments, the methods of the present invention
reduce, ameliorate, or eliminate one or more symptom(s) associated
with a herein-described disease, disorder, or condition. Exemplary
symptoms include, but are not limited to, diarrhea, bloody stool,
mouth sores, perianal disease, abdominal pain, abdominal cramping,
fever, fatigue, weight loss, iron deficiency, anemia, appetite
loss, weight loss, anorexia, delayed growth, delayed pubertal
development, and inflammation of the skin, eyes, joints, liver, and
bile ducts.
[0310] In one aspect, a method comprises administering a
therapeutic composition orally, by enema, or via rectal
suppository. In one aspect, a pharmaceutical composition is
formulated as a geltab, pill, microcapsule, capsule, or tablet. In
one aspect, a therapeutic composition is formulated as an enteric
coated capsule or microcapsule, acid-resistant capsule or
microcapsule, or formulated as part of or administered together
with a food, a food additive, a dairy-based product, a soy-based
product or a derivative thereof, a jelly, or a yogurt. In another
aspect, a therapeutic composition is formulated as an
acid-resistant enteric coated capsule. A therapeutic composition
can be provided as a powder for sale in combination with a food or
drink. A food or drink can be a dairy-based product or a soy-based
product. In another aspect, a food or food supplement contains
enteric-coated and/or acid-resistant microcapsules containing a
therapeutic composition.
[0311] Any aspect or embodiment disclosed herein can be combined
with any other aspect or embodiment as disclosed herein.
Definitions
[0312] As used herein, "isolated" or "purified" refers to a
bacterium or other entity or substance that has been (1) separated
from at least some of the components with which it was associated
when initially produced (whether in nature or in an experimental
setting), and/or (2) produced, prepared, purified, and/or
manufactured by the hand of man. Isolated or purified bacteria can
be separated from at least about 10%, about 20%, about 30%, about
40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more
of the other components with which they were initially
associated.
[0313] As used herein, "microbiota," and "flora" refer to a
community of microbes that live in or on a subject's body, both
sustainably and transiently, including eukaryotes, archaea,
bacteria, and viruses (including bacterial viruses (i.e., phage)).
A non-selected fecal microbiota refers to a community or mixture of
fecal microbes derived from a donor's fecal sample without
selection and substantially resembling microbial constituents and
population structure found in such fecal sample.
[0314] As used herein, "gut dysbiosis" refers to an imbalance,
maladaptation, and/or reduced diversity in the microbiota in a
subject's digestive system. For example, a part of the gut flora is
unbalanced, with normally dominating species, i.e., beneficial
bacteria, becoming underrepresented (and/or less metabolically
active) and outcompeted by contained species, e.g., pathogenic
and/or antibiotic-resistant bacteria, which proliferate to fill the
void.
[0315] As used herein, examples of a "side effect of an anti-cancer
therapeutic agent" and a "side effect of an anti-cancer therapy"
include abdominal pain, anemia and low blood counts, appetite loss,
autoimmune effects, bleeding and bruising (thrombocytopenia),
cancer, changes in mood or thinking, colonization by pathogenic
bacteria, constipation, cough, dehydration, delirium,
diabetes-related symptoms, diarrhea, dry mouth or xerostomia,
eating problems, edema, falling, fatigue, fertility issues, fever,
flu-like symptoms, fluid in the abdomen or ascites,
gastrointestinal (GI) mucositis, gut dysbiosis, hair loss
(alopecia), hand-foot syndrome or palmar-plantar
erythrodysesthesia, headache, hearing problems, high or low blood
pressure, hormone changes, hiccups, hypercalcemia, infection and
neutropenia, infection by pathogenic bacteria, inflammatory bowel
disease, irritable bowel syndrome, leg cramps, lymphedema, memory
or concentration problems, mouth and throat problems, nausea and
vomiting, nerve problems (peripheral neuropathy), obesity,
osteoporosis, ostomies, pain, seizures, sexual health issues,
shortness of breath, sinus congestion, skin and nail changes, sleep
problems, stool or urine changes, sweating, swelling, ulcerative
colitis, urinary and bladder problems, weight gain from retaining
fluid, and/or weakness. In embodiments, a side effect of the
anti-cancer therapeutic agent and/or anti-cancer therapy is caused
by gut dysbiosis; it has been reported that chemotherapy, for
example, is associated with reduced diversity in the gut
microbiome. Thus, "treating or preventing or reducing a side
effect" refers to decreasing the severity of a side effect and up
to eliminating the side effect, e.g., in part, by
repairing/repopulating his/her gut microbiome after receiving the
anti-cancer therapeutic agent and/or anti-cancer therapy.
[0316] As used herein, "increase[ing] efficacy of an anti-cancer
therapeutic agent and/or anti-cancer therapy" refers to the ability
of a microbial composition or method using same to promote the
beneficial and desired effects of an anti-cancer therapeutic agent
and/or anti-cancer therapy, i.e., killing cancer cells, reducing
tumor size, and/or simulating an immune response against a cancer
cell or tumor.
[0317] As used herein, "spore" or a population of "spores" includes
bacteria (or other single-celled organisms) that are generally
viable, more resistant to environmental influences such as heat and
bactericidal agents than vegetative forms of the same bacteria, and
typically capable of germination and out-growth. "Spore-formers" or
bacteria "capable of forming spores" are those bacteria containing
the genes and other necessary abilities to produce spores under
suitable environmental conditions.
[0318] In embodiments, the subject, e.g., a human, is refractory
and/or non-responsive to a treatment directed to a checkpoint
molecule. In embodiments, the treatment directed to a checkpoint
molecule comprises administration of Keytruda (Pembrolizumab),
Opdivo (Nivolumab), Yervoy (Ipilimumab), Tecentriq (atezolizumab),
Bavencio (avelumab), or lmfinzi (durvalumab).
[0319] As used herein, the term "treating" refers to (i) completely
or partially inhibiting a disease, disorder or condition, for
example, arresting its development; (ii) completely or partially
relieving a disease, disorder or condition, for example, causing
regression of the disease, disorder and/or condition; or (iii)
completely or partially preventing a disease, disorder or condition
from occurring in a patient that may be predisposed to the disease,
disorder and/or condition, but has not yet been diagnosed as having
it. Similarly, "treatment" refers to both therapeutic treatment and
prophylactic or preventative measures.
[0320] As used herein, the term "substantially", when used to
modify a quality, generally allows certain degree of variation
without that quality being lost. For example, in certain aspects
such degree of variation can be less than 0.1%, about 0.1%, about
0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,
about 0.8%, about 0.9%, about 1%, between 1-2%, between 2-3%,
between 3-4%, between 4-5%, or greater than 5%.
[0321] In some embodiments, the terms "patient" and "subject" are
used interchangeably. In some embodiments, the subject and/or
animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog,
cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as
a monkey, chimpanzee, or baboon. In other embodiments, the subject
and/or animal is a non-mammal, such, for example, a zebrafish.
[0322] In various embodiments, methods of the invention are useful
in treatment a human subject. In some embodiments, the human is a
pediatric human. In other embodiments, the human is an adult human.
In other embodiments, the human is a geriatric human. In other
embodiments, the human may be referred to as a patient. In some
embodiments, the human is a female. In some embodiments, the human
is a male.
[0323] In certain embodiments, the human has an age in a range of
from about 1 to about 18 months old, from about 18 to about 36
months old, from about 1 to about 5 years old, from about 5 to
about 10 years old, from about 10 to about 15 years old, from about
15 to about 20 years old, from about 20 to about 25 years old, from
about 25 to about 30 years old, from about 30 to about 35 years
old, from about 35 to about 40 years old, from about 40 to about 45
years old, from about 45 to about 50 years old, from about 50 to
about 55 years old, from about 55 to about 60 years old, from about
60 to about 65 years old, from about 65 to about 70 years old, from
about 70 to about 75 years old, from about 75 to about 80 years
old, from about 80 to about 85 years old, from about 85 to about 90
years old, from about 90 to about 95 years old or from about 95 to
about 100 years old.
[0324] As used in this Specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise.
[0325] Unless specifically stated or obvious from context, as used
herein, the term "or" is understood to be inclusive and covers both
"or" and "and".
[0326] Unless specifically stated or obvious from context, as used
herein, the term "about" is understood as within a range of normal
tolerance in the art, for example within (plus or minus) 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the
stated value. Unless otherwise clear from the context, all
numerical values provided herein are modified by the term
"about."
[0327] The terms "one or more", "at least one", and the like are
understood to include but not be limited to at least 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,
120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,
146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900,
1000, 2000, 3000, 4000, 5000 or more and any number in between.
[0328] Conversely, the term "no more than" includes each value less
than the stated value.
[0329] The terms "plurality", "at least two", "two or more", "at
least second", and the like, are understood to include but not
limited to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,
50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,
84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,
100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,
113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125,
126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138,
139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200,
300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or
more and any number in between.
[0330] The term "greater than" and the like, is understood to
include values greater than the stated by at least 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,
120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,
146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900,
1000, 2000, 3000, 4000, 5000 or more and any number in between.
[0331] A stated range is understood to be any value between and at
the limits of the stated range. As examples, a range between 1 and
5 includes 1, 2, 3, 4, and 5; a range between 1 and 10 includes 1,
2, 3, 4, 5, 6, 7, 8, 9, and 10; and a range between 1 and 100
includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,
52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,
69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,
86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100.
[0332] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
other probes, compositions, methods, and kits similar, or
equivalent, to those described herein can be used in the practice
of the present invention, the preferred materials and methods are
described herein. It is to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting.
EXAMPLES
Example 1: Determination of Useful Bacteria in a Bacterial Mixture
of the Present Invention
[0333] Tables 5 and 6 (above) were created based upon analyses
using 16S rRNA sequencing data from public and private sources to
identify drivers of ARB decolonization.
[0334] Some of the operational taxonomic units (OTUs) were
identified because they are present in healthy stool donors and the
family or genus they belong to was at least five-fold enriched in
stool donors compared to patients pre-FMT, and in a receiver
operator curve (ROC) plot, the area under the curve (AUC) was
greater than or equal to 0.6, showing that the presence/absence of
these families and genera can predict whether a sample is from a
donor or from a patient pre-FMT. Some of the OTUs were identified
because they are present in healthy stool donors and the family or
genus they belong to was enriched in patients who did not become
dominated with Enterococcus or pathogenic Gram-negative bacteria
compared to those who became dominated, and in a ROC plot, the AUC
was greater than or equal to 0.6, showing that the presence/absence
of these families and genera can predict whether a patient's gut
will become dominated by enteric pathogens. Patients had received
or were undergoing stem cell transplantation as part of a treatment
for leukemia, lymphoma, multiple myeloma or myelodysplastic
syndrome.
[0335] Other OTUs were identified because they are present in
healthy stool donors and the family or genus they belong to was
enriched in people with a C. difficile infection who were not
colonized with Extended Spectrum Beta-Lactamase producing
Enterobacteriaceae (ESBL-E) compared to those who became colonized,
and in a ROC plot, the AUC was greater than or equal to 0.6,
showing that the presence/absence of these families and genera can
predict whether a patient will become colonized with ESBL-E.
[0336] Four datasets were used in these analyses: (1) Taur Y,
Xavier J, Lipuma L, Caries Ubeda, Goldberg J, Gobourne A, Lee Y,
Dubin K, Socci N, Viale A, Perales M-A, Jenq R, Brink M, Pamer E.
Intestinal Domination and the Risk of Bacteremia in Patients
Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. Clin
Infect Dis. 2012; 55(7):905-914. PMCID: PMC3657523; (2) Gosalbes M
J, Vazquez-Castellanos J F, Angebault C, Woerther P-L, Ruppe E,
Ferr s M L, Latorre A, Andremont A, Moya A. Carriage of
Enterobacteria Producing Extended-Spectrum .beta.-Lactamases and
Composition of the Gut Microbiota in an Amerindian Community.
Antimicrob Agents Chemother. 2015 Dec. 31; 60(1):507-514. PMCID:
PMC4704183; (3) Multicenter retrospective study assessing efficacy
of FMT for VRE decolonization in patients with rCDI who were also
colonized with VRE; and (4) 16S sequencing was performed on samples
from 63 healthy and extensively-screened stool donors.
[0337] FIG. 1 is a pie chart showing percentage of all OTUs in
GreenGenes database that are found in a healthy human gut and that
are included in Table 5. The GreenGenes database contains sequence
data corresponding to almost 100,000 unique 16S sequences from
different bacterial strains that have been sequenced. See, the
World Wide Web (www) at greengenes.lbl.gov. FIG. 1 shows the
fraction of all OTUs found in the GreenGenes database that are
found in the human gut and that are relevant to the present
invention. As shown in FIG. 1, 94.6% of of all OTUs in the
GreenGenes database are not found in the healthy human gut; 4.3% of
all OTUs in the GreenGenes database are found in the healthy human
gut; and 1.2% of all OTUs in the GreenGenes database that are
listed in Table 5.
Example 2. Development of Bacterial Mixtures
[0338] A product candidate is being developed which includes a
novel mixture of commensal bacterial strains that can decolonize
and/or eradicate and/or reduce the load of antibiotic-resistant
enteric pathogens in the gut.
[0339] Bacterial strains may be included in a mixture based on
their abundance in donors whose stool was used for successful fecal
microbiota transplants (FMTs) in a patient suffering from a gut
dysbiosis disorder, e.g., caused by a previous or current
anti-cancer therapy. Additionally, bacterial strains may be
included in a mixture due to their ability to colonize the mucosa,
to complement the capacity of a functionally deficient microbial
community (e.g., the microbial community of a patient infected
and/or colonized by a pathogenic bacteria), to produce levels of
SCFAs comparable to healthy individuals, to decolonize a pathogenic
bacterium, to directly compete with the ARB for a niche and/or for
nutrients, to directly compete with the pathogenic bacteria for a
niche and/or for nutrients, to directly inhibit a pathogenic
bacterium through production of a secreted product, to directly
inhibit an antibiotic-resistant bacterium (ARB) through production
of a secreted product, to enable mucosal healing, improve mucosal
barrier function, and/or to reduce inflammation, to enhance
production of SCFAs, to eradicate a pathogenic bacterium, to
improve mucosal barrier function, and/or, to promote restoration of
mucosal barrier functions, and/or to reduce inflammation.
[0340] Certain bacterial strains are included in a mixture based
upon their 16S rRNA sequence identity. For example, the mixture
includes one or more bacterial strains having a 16S rRNA sequence
that is at least about 80% identical to the 16S rRNA sequence of
any one of the operational taxonomic units (OTUs) provided in Table
5 or Table 6. For example, the mixture may include one or more
bacterial strains having a 16S rRNA sequence that is at least about
80%, about 81%, about 82%, about 83%, about 84%, about 85%, about
86%, about 87%, about 88%, about 89%, about 90%, about 91%, about
92%, about 93%, about 94%, about 95%, about 96%, about 97%, about
98%, about 99%, or about 100% identical with the 16S rRNA sequence
of any one of the operational taxonomic units (OTUs) provided in
Table 5 or Table 6.
[0341] Certain mixtures of bacterial strains are substantially
complete or non-selected fecal microbiota preparations (e.g., from
a single donor), which generally comprises a full complement of
functional microorganisms found in feces of one or more healthy
humans. Such mixtures of bacterial strains may be supplemented with
one or more strains listed in Table 5 or Table 6 and/or one or more
strains having a 16S rRNA sequence that is at least about 95%
identical with the 16S rRNA sequence of any one of the strains
listed in Table 5 or Table 6.
[0342] Other mixtures of bacterial strains comprise "less than the
full complement" of functional microorganisms found in feces of one
healthy human or in feces of more than one healthy human donor.
These bacterial mixtures omit at least one bacterial strain from
the full complement. Such mixtures of bacterial strains may be
supplemented with one or more strains listed in Table 5 or Table 6
and/or one or more strains having a 16S rRNA sequence that is at
least about 95% identical with the 16S rRNA sequence of any one of
the strains listed in Table 5 or Table 6.
[0343] Some bacterial strains in a mixture are directly obtained
from human feces (i.e., from a suitable and healthy donor); Some of
those strains may isolated or purified from its source material,
i.e., separated from at least some of the components with which
they were associated when initially produced (e.g., nature (from
feces))
[0344] Some bacterial strains in a mixture are indirectly obtained
from human feces and/or are obtained independent of human feces
(e.g., from a bacterial cell bank or from a laboratory stock).
Example 3: Production of a Pharmaceutical Composition
[0345] Strains selected in Example 1 and/or Example 2 may be
independently cultured and mixed together before administration.
Cultured strains are independently grown in supportive media, e.g.
at 37.degree. C., pH 7, in a GMM or other animal-products-free
medium, pre-reduced with 1 g/L cysteine.HCl. After each strain
reaches a sufficient biomass, it is optionally preserved for
banking by adding 15% glycerol and then frozen at -80.degree. C. in
1 ml cryotubes.
[0346] Each strain may then be cultivated to a concentration of
about 10.sup.10 CFU/mL, then concentrated 20-fold by tangential
flow microfiltration; the spent medium is exchanged by diafiltering
with a preservative medium consisting of 2% gelatin, 100 mM
trehalose, and 10 mM sodium phosphate buffer, or other suitable
preservative medium. The suspension is freeze-dried to a powder and
titrated.
[0347] After drying, the powder is blended with microcrystalline
cellulose and magnesium stearate and formulated into a 250 mg
gelatin capsule containing 10 mg of lyophilized powder (10.sup.8 to
10.sup.11 bacteria), 160 mg microcrystalline cellulose, 77.5 mg
gelatin, and 2.5 mg magnesium stearate.
Example 4: Methods of Treatment
[0348] A subject having gut dysbiosis is administered a
pharmaceutical composition comprising a bacterial mixture of the
present invention to treat the gut dysbiosis.
[0349] For subjects who have gut dysbiosis as a side effect of an
anti-cancer therapeutic agent and/or a side effect of an
anti-cancer therapy, the pharmaceutical composition helps reduce or
treating the side effect.
[0350] For subjects who have undergone or are undergoing an
anti-cancer therapeutic agent and/or a side effect of an
anti-cancer therapy, the pharmaceutical composition increases the
efficacy of the anti-cancer therapeutic agent and/or anti-cancer
therapy.
Example 5: Methods of Prevention
[0351] A subject at risk for gut dysbiosis is administered a
pharmaceutical composition comprising a bacterial mixture of the
present invention to prevent gut dysbiosis.
[0352] For subjects who are at risk for gut dysbiosis as a side
effect of an anti-cancer therapeutic agent and/or a side effect of
an anti-cancer therapy, the pharmaceutical composition helps
prevents the likelihood of getting the side effect.
EQUIVALENTS
[0353] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth and as follows in the scope of the appended
claims.
[0354] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
REFERENCES
[0355] 1. Antibiotic Resistance Threats in the United States, 2013
[Internet]. US Department of Health and Human Services, Centers for
Disease Control and Prevention; 2013. Available from: the World
Wide Web (www) at
cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf [0356] 2. Stone
P W. Economic burden of healthcare-associated infections: an
American perspective. Expert Rev Pharmacoecon Outcomes Res. 2009
October; 9(5):417-422. PMCID: PMC2827870 [0357] 3. Pamer E G.
Resurrecting the intestinal microbiota to combat
antibiotic-resistant pathogens. Science. 2016; 352(6285):535-8.
PMCID: PMC4984266 [0358] 4. Abt M, Pamer E. Commensal bacteria
mediated defenses against pathogens. Curr Opin Immunol. 2014;
29:16-22. PMCID: PMC4132187 [0359] 5. Becattini S, Taur Y, Pamer E
G. Antibiotic-Induced Changes in the Intestinal Microbiota and
Disease. Trends Mol Med. 2016; 22(6):458-78. PMCID: PMC4885777
[0360] 6. Carlet J. The gut is the epicentre of antibiotic
resistance. Antimicrob Resist Infect Control. 2012; 1:39. [0361] 7.
Buffie C, Pamer E. Microbiota-mediated colonization resistance
against intestinal pathogens. Nat Rev Immunol. 2013; 13(14790-801.
PMCID: PMC4194195 [0362] 8. Martina S-C, Raffatellu M. No Vacancy:
How Beneficial Microbes Cooperate with Immunity To Provide
Colonization Resistance to Pathogens. J Immunol. 2015;
194(9):4081-4087. PMCID: PMC4402713 [0363] 9. Ubeda C, Taur Y, Jenq
R, Equinda M, Son T, Samstein M, Viale A, Socci N, Brink M, Kamboj
M, Pamer E. Vancomycin-resistant Enterococcus domination of
intestinal microbiota is enabled by antibiotic treatment in mice
and precedes bloodstream invasion in humans. J Clin Invest. 2010;
120(12):4332-4341. PMCID: PMC2993598 [0364] 10. Ziakas P D, Thapa
R, Rice L B, Mylonakis E. Trends and significance of VRE
colonization in the ICU: a meta-analysis of published studies. PloS
One. 2013; 8(9):e75658. PMCID: PMC3785502 [0365] 11. Hendrix C W,
Hammond J M, Swoboda S M, Merz W G, Harrington S M, Perl T M, Dick
J D, Borschel D M, Halczenko P W, Pelz R K, Rocco L E, Conway J E,
Brower R G, Lipsett P A. Surveillance strategies and impact of
vancomycin-resistant enterococcal colonization and infection in
critically ill patients. Ann Surg. 2001 February; 233(2):259-265.
PMCID: PMC1421209 [0366] 12. Horwitz D, McCue T, Mapes A C, Ajami N
J, Petrosino J F, Ramig R F, Trautner B W. Decreased microbiota
diversity associated with urinary tract infection in a trial of
bacterial interference. J Infect. 2015 September; 71(3):358-367.
PMCID: PMC4529357 [0367] 13. Safdar N, Sengupta S, Musuuza J S,
Juthani-Mehta M, Drees M, Abbo L M, Milstone A M, Furuno J P,
Varman M, Anderson D J, Morgan D J, Miller L G, Snyder G M, and the
SHEA Research Committee. Status of the Prevention of
Multidrug-Resistant Organisms in International Settings: A Survey
of the Society for Healthcare Epidemiology of America Research
Network. Infect Control Hosp Epidemiol. 2016 Nov. 7; 1-8. PMID:
27817759 [0368] 14. Abad C, Fearday A, Safdar N. Adverse effects of
isolation in hospitalised patients: a systematic review. J Hosp
Infect. 2010; 76(2):97-102. PMID: 20619929 [0369] 15. Bowling J E,
Taylor B S. Isolation Precautions for Hospitalized Patients: The
Challenges of Identifying
[0370] Unintended Individual Consequences and Measuring the
Prevention of Community Harm. J Gen Intern Med. 2016 Nov. 18; 1-3.
[0371] 16. Guilley-Lerondeau B, Bourigault C, Buttes A-C G des,
Birgand G, Lepelletier D. Adverse effects of isolation: a
prospective matched cohort study including 90 direct interviews of
hospitalized patients in a French University Hospital. Eur J Clin
Microbiol Infect Dis. 2017 Jan. 1; 36(1):75-80. [0372] 17. Kassam
Z, Lee C H, Yuan Y, Hunt R H. Fecal microbiota transplantation for
Clostridium difficile infection: systematic review and
meta-analysis. Am J Gastroenterol. 2013 April; 108(4):500-508.
PMID: 23511459 [0373] 18. Fischer M, Sipe B, Cheng Y-W, Phelps E,
Rogers N, Sagi S, Bohm M, Xu H, Kassam Z. Fecal microbiota
transplant in severe and severe-complicated Clostridium difficile:
A promising treatment approach. Gut Microbes. 2016 Dec. 21; 1-14. P
M I D: 28001467 [0374] 19. Singh R, Nood E, Nieuwdorp M, Dam B,
Berge I, Geerlings S, Bemelman F. Donor feces infusion for
eradication of Extended Spectrum beta-Lactamase producing
Escherichia coli in a patient with end stage renal disease. Clin
Microbiol Infec. 2014; 20(11):0977-0978. PMID: 24845223 [0375] 20.
Garcia-Fernandez S, Morosini M-I, Cobo M, Foruny J R,
Lopez-Sanroman A, Cobo J, Romero J, Canton R, Del Campo R. Gut
eradication of VIM-1 producing ST9 Klebsiella oxytoca after fecal
microbiota transplantation for diarrhea caused by a Clostridium
difficile hypervirulent R027 strain. Diagn Microbiol Infect Dis.
2016 December; 86(4):470-471. PMID: 27712927 [0376] 21. Millan B,
Park H, Hotte N, Mathieu O, Burguiere P, Tompkins T, Kao D, Madsen
K. Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in
Patients With Recurrent Clostridium difficile Infection. Clin
Infect Dis. 2016; 62(12):1479-1486. PMID: 27025836 [0377] 22.
Lagier J, Million M, Fournier P, Brouqui P, Raoult D. Faecal
microbiota transplantation for stool decolonization of OXA-48
carbapenemase-producing Klebsiella pneumoniae. J Hosp Infect. 2015;
90(2):173-4. PMID: 25913649 [0378] 23. Bili ski J, Grzesiowski P,
Muszy ski J, Wroblewska M, M dry K, Robak K, Dzieci tkowski T,
Wieslaw W-J, Basak G. Fecal Microbiota Transplantation Inhibits
Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in
an Immunocompromised Host. Arch Immunol Ther Ex. 2016;
64(3):255-258. PMID: 26960790 [0379] 24. Bilinski J, Grzesiowski P,
Sorensen N, Madry K, Muszynski J, Robak K, Wroblewska M,
Dzieciatkowski T, Dulny G, Dwilewicz-Trojaczek J,
Wiktor-Jedrzejczak W, Basak G W. Fecal Microbiota Transplantation
in Patients with Blood Disorders Inhibits Gut Colonization with
Antibiotic-Resistant Bacteria: Results of a Prospective,
Single-Center Study. Clin Infect Dis Off Publ Infect Dis Soc Am.
2017 Mar. 24; PMID: 28369341 [0380] 25. Freedman A. Use of Stool
Transplant to Clear Fecal Colonization with Carbapenem-Resistant
Enterobacteraciae (CRE): Proof of Concept. Idsa; 2014 [cited 2017
Mar. 30]. Available from:
https://idsa.confex.com/idsa/2014/webprogram/Paper47124.html [0381]
26. Davido B, Batista R, Michelon H, Lepainteur M, Bouchand F,
Lepeule R, Salomon J, Vittecoq D, Duran C, Escaut L, Sobhani I,
Paul M, Lawrence C, Perronne C, Chast F, Dinh A. Is faecal
microbiota transplantation an option to eradicate highly
drug-resistant enteric bacteria carriage? J Hosp Infect. 2017 Apr.
1; 95(4):433-437. PMID: 28237504 [0382] 27. Sohn K M, Cheon S, Kim
Y-S. Can Fecal Microbiota Transplantation (FMT) Eradicate Fecal
Colonization With Vancomycin-Resistant Enterococci (VRE)? Infect
Control Amp Hosp Epidemiol. 2016 January; 1-2. [0383] 28. Jouhten
H, Mattila E, Arkkila P, Satokari R. Reduction of Antibiotic
Resistance Genes in Intestinal Microbiota of Patients With
Recurrent Clostridium difficile Infection After Fecal Microbiota
Transplantation. Clin Infect Dis. 2016; 63(5):710-1. PMID: 27317794
[0384] 29. Dubberke E R, Mullane K M, Gerding D N, Lee C H, Louie T
J, Guthertz H, Jones C. Clearance of Vancomycin-Resistant
Enterococcus Concomitant With Administration of a Microbiota-Based
Drug Targeted at Recurrent Clostridium difficile Infection. Open
Forum Infect Dis. 2016; 3(3):ofw133. [0385] 30. Smith M. Clearance
of Vancomycin-Resistant Enterococcus Colonization with Fecal
Microbiota Transplantation among Patients with Recurrent
Clostridium difficile Infection. Idsa; 2016 [cited 2016 Oct. 21].
Available from:
https://idsa.confex.com/idsa/2016/webprogram/Paper59960.html [0386]
31. Khanna S, Pardi D S, Kelly C R, Kraft C S, Dhere T, Henn M R,
Lombardo M-J J, Vulic M, Ohsumi T, Winkler J, Pindar C, H M
Barbara, Pomerantz R J, Aunins J G, Cook D N, Hohmann E L. A Novel
Microbiome Therapeutic Increases Gut Microbial Diversity and
Prevents Recurrent Clostridium difficile Infection. J Infect Dis.
2016; 214(2):173-81. PMID: 26908752 [0387] 32. Jang M-O, An J, Jung
S-I, Park K-H. Refractory Clostridium difficile Infection Cured
With Fecal Microbiota Transplantation in Vancomycin-Resistant
Enterococcus Colonized Patient. Intest Res. 2014; 13(1):80-84.
PMCID: PMC4316227 [0388] 33. Nancy C-C, Sullivan E, Gonzalo B-L.
Fecal Microbiota Transplantation and Successful Resolution of
Multidrug-Resistant-Organism Colonization. J Clin Microbiol. 2015;
53(6):1986-1989. PMID: 25878340 [0389] 34. Stripling J, Kumar R,
Baddley J W, Nellore A, Dixon P, Howard D, Ptacek T, Lefkowitz E J,
Tallaj J A, Benjamin W H, Morrow C D, Rodriguez J. Loss of
Vancomycin-Resistant Enterococcus Fecal Dominance in an Organ
Transplant Patient With Clostridium difficile Colitis After Fecal
Microbiota Transplant. Open Forum Infect Dis. 2015; 2(2):ofv078.
PMCID: PMC4498259 [0390] 35. Gilmore M, Rauch M, Ramsey M, Himes P,
Varahan S, Manson J, Lebreton F, Hancock L. Pheromone killing of
multidrug-resistant Enterococcus faecalis V583 by native commensal
strains. P Natl Acad Sci Usa. 2015; 112(23):7273-8. PMCID:
PMC4466700 [0391] 36. Gaca A, Gilmore M. Killing of VRE
Enterococcus faecalis by commensal strains: Evidence for evolution
and accumulation of mobile elements in the absence of competition.
Gut Microbes. 2016; 7(1):90-96. PMCID: PMC4856443 [0392] 37.
Sassone-Corsi M, Nuccio S-P, Liu H, Hernandez D, Vu C T, Takahashi
A A, Edwards R A, Raffatellu M. Microcins mediate competition among
Enterobacteriaceae in the inflamed gut. Nature. 2016 Dec. 8;
540(7632):280-283. [0393] 38. Hecht A L, Casterline B W, Earley Z
M, Goo Y A, Goodlett D R, Bubeck Wardenburg J. Strain competition
restricts colonization of an enteric pathogen and prevents colitis.
EMBO Rep. 2016; 17(9):1281-91. PMCID: PMC5007561 [0394] 39.
McKenney E S, Kendall M M. Microbiota and pathogen "pas de deux":
setting up and breaking down barriers to intestinal infection.
Pathog Dis. 2016; 74(5). PMID: 27252177 [0395] 40. Ubeda C, Bucci
V, Caballero S, Djukovic A, Toussaint N, Equinda M, Lipuma L, Ling
L, Gobourne A, No D, Taur Y, Jenq R, Brink M, Xavier J, Pamer E.
Intestinal Microbiota Containing Barnesiella Species Cures
Vancomycin-Resistant Enterococcus faecium Colonization. Infect
Immun. 2013; 81(3):965-973. PMCID: PMC3584866 [0396] 41. Kinnebrew
M, Ubeda C, Zenewicz L, Smith N, Flavell R, Pamer E. Bacterial
flagellin stimulates Toll-like receptor 5-dependent defense against
vancomycin-resistant Enterococcus infection. J Infect Dis. 2010;
201(4):534-43. PMCID: PMC2811237 [0397] 42. Desai M S, Seekatz A M,
Koropatkin N M, Kamada N, Hickey C A, Wolter M, Pudlo N A, Kitamoto
S, Terrapon N, Muller A, Young V B, Henrissat B, Wilmes P,
Stappenbeck T S, Nunez G, Martens E C. A Dietary Fiber-Deprived Gut
Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen
Susceptibility. Cell. 2016 Nov. 17; 167(5):1339-1353.e21. [0398]
43. Earle K A, Billings G, Sigal M, Lichtman J S, Hansson G C,
Elias J E, Amieva M R, Huang K C, Sonnenburg J L. Quantitative
Imaging of Gut Microbiota Spatial Organization. Cell Host Microbe.
2015 Oct. 14; 18(4):478-488. PMID: 26439864 [0399] 44. Goverse G,
Molenaar R, Macia L, Tan J, Erkelens M N, Konijn T, Knippenberg M,
Cook ECL, Hanekamp D, Veldhoen M, Hartog A, Roeselers G, Mackay C
R, Mebius R E. Diet-Derived Short Chain Fatty Acids Stimulate
Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic
Cells. J Immunol. 2017 Jan. 18; 1600165. PMID: 28100682 [0400] 45.
Wu W, Sun M, Chen F, Cao A T, Liu H, Zhao Y, Huang X, Xiao Y, Yao
S, Zhao Q, Liu Z, Cong Y. Microbiota metabolite short-chain fatty
acid acetate promotes intestinal IgA response to microbiota which
is mediated by GPR43. Mucosal Immunol [Internet]. 2016 Dec. 14
[cited 2017 Jan. 24]; Available from: the World Wide Web (www) at
nature.com/doifinder/10.1038/mi.2016.114 [0401] 46. Olsan E E et
al. Colonization resistance: the deconvolution of a complex trait.
2017. Journal of Biological Chemistry 292(21): 8577-8581. [0402]
47. Meynell G G. Antibacterial mechanisms of the mouse gut. II. The
role of Eh and volative fatty acids in the normal gut. 1963.
British journal of experimental pathology 44: 209-219. [0403] 48.
Winter S E et al. The dynamics of gut-associated microbial
communities during inflammation. 2013. EMPO
[0404] Rep 14: 319-327. [0405] 49. Winter S E et al. Host-derived
nitrate boosts growth of E. coli in the inflamed gut. 2013. Science
339: 708-711. [0406] 50. Spees A M et al. Streptomycin-induced
inflammation enhances Escherichia coli gut colonization through
nitrate respiration. 2013. MBio 4: e00430 [0407] 51. Garner C D et
al. Perturbation of the small intestine microbial ecology by
streptomycin alters pathology in a Salmonella enterica serovar
typhimurium murine model of infection. 2009. Infection and Immunity
77: 2691-2702. [0408] 52. Smith P M et al. The microbial
metabolites, short-chain fatty acids, regulate colonic Treg cell
homeostasis. 2013. Science 341: 569-573. [0409] 53. Rivera-Chavez F
et al. Depletion of butyrate-producing Clostridia from the gut
microbiota drives an aerobic luminal expansion of Salmonella. 2016.
Cell Host and Microbe 19: 443-454. [0410] 54. Itoh K and Freter R.
Control of Escherichia coli populations by a combination of
indigenous Clostridia and Lactobacilli in gnotobiotic mice and
continuous-flow cultures. 1989. Infection and Immunity 57: 559-565.
[0411] 55. Donohoe D R et al. Microbial regulation of glucose
metabolism and cell-cycle progression in mammalian colonocytes.
2012. PLoS One 7: e46589. [0412] 56. Kelly C J et al. Crosstalk
between microbiota-derived short-chain fatty acids and intestinal
epithelial HIF augments tissue barrier function. 2015. Cell Host
and Microbe 17: 662-671. [0413] 57. Jones S A et al. Anaerobic
respiration of Escherichia coli in the mouse intestine. 2011.
Infection and Immunity 79: 4218-4226. [0414] 58. Kinnebrew M et al.
Bacterial flagellin stimulates TLRS-dependent defense against
vancomycin-resistant Enterococcus infection. 2010. Journal of
Infectious Disease 201(4): 534-543. [0415] 59. Artis D.
Epithelial-cell recognition of commensal bacteria and maintenance
of immune homeostasis in the gut. 2008. Nature Reviews Immunology
8:411-420. [0416] 60. Vaishnava S et al. Paneth cells directly
sense gut commensals and maintain homeostasis at the intestinal
host-microbial interface. 2008. PNAS. [0417] 61. Macpherson A J et
al. Interactions between commensal intestinal bacteria and the
immune system. 2004.
[0418] Nature Reviews Immunology 4: 478-485. [0419] 62.
Rakoff-Nahoum S et al. Recognition of commensal microflora by
toll-like receptors is required for intestinal homeostasis. 2004.
Cell 118:229-241. [0420] 63. Pamer E G. Immune responses to
commensal and environmental microbes. 2007. Nature Immunology
8:1173-1178. [0421] 64. Cash H L et al. Symbiotic bacteria direct
expression of an intestinal bactericidal lectin. 2006. Science 313:
1126-1130. [0422] 65. Ayabe T et al. Secretion of microbicidal
alpha-defensins by intestinal Paneth cells in response to bacteria.
2000. Nature Immunology 1:113-118. [0423] 66. Vora P et al.
Beta-defensin-2 expression is regulated by TLR signaling in
intestinal epithelial cells. 2004. Journal of Immunology
173:5398-5405. [0424] 67. Kolls J K et al. Cytokine-mediated
regulation of antimicrobial proteins. 2008. Nature Reviews
Immunology 8: 829-835. [0425] 68. Brandi K et al. MyD88-mediated
signals induce the bactericidal lectin Reglllgamma and protect mice
against intestinal Listeria monocytogenes infection. 2007. Journal
of Experimental Medicine 204: 1891-1900. [0426] 69. Brandi K et al.
Vancomycin-resistant enterococci exploit antibiotic-induced innate
immune deficits 2008. Nature 455: 804-807. [0427] 70. Charlier C,
Cretenet M, Even S, Le Loir Y (2009) Interactions between
Staphylococcus aureus and lactic acid bacteria: an old story with
new perspectives. Int J Food Microbiol 131:30-39 [0428] 71. Reid G,
Kim S O, Ko''hler G A (2006) Selecting, testing and understanding
probiotic microorganisms. FEMS Immunol Med Microbiol 46:149-157
[0429] 72. Matu M N, Orinda G O, Njagi ENM, Cohen C R, Bukusi E A
(2010) In vitro inhibitory activity of human vaginal lactobacilli
against pathogenic bacteria associated with bacterial vaginosis in
Kenyan women. Anaerobe 16:210-215 [0430] 73. Karaoglu S, A, Aydin
F, Kilic, S S, Kilic, A O (2002) Antimicrobial activity and
characteristics of bacteriocins produced by vaginal lactobacilli.
Turk J Med Sci 33:7-13 [0431] 74. Zarate G, Nader-Macias M E (2006)
Influence of probiotic vaginal lactobacilli on in vitro adhesion of
urogenital pathogens to vaginal epithelial cells. Lett Appl
Microbiol 43:174-180 [0432] 75. Boris S, Suarez J E, Vazquez F,
Barbes C (1998) Adherence of human vaginal lactobacilli to vaginal
epithelial cells and interaction with uropathogens. Infect Immun
66:1985-1989
INCORPORATION BY REFERENCE
[0433] All patents and publications referenced herein are hereby
incorporated by reference in their entireties.
[0434] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention.
[0435] As used herein, all headings are simply for organization and
are not intended to limit the disclosure in any manner. The content
of any individual section may be equally applicable to all
sections.
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
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An electronic copy of the "Sequence Listing" will also be available
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0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20200093870A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References